bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence that Clostridium perfringens Enterotoxin-Induced Intestinal Damage and Enterotoxemic Death in Mice Can Occur Independently of Intestinal Caspase-3 Activation
Authors: Freedman John C. , Navarro Mauricio A. , Morrell Eleonora , Beingesser Juliann , Shrestha Archana , McClane Bruce A. , Uzal Francisco A. 
Published: April 2018

ABSTRACT

Clostridium perfringens
enterotoxin (CPE) is responsible for the gastrointestinal symptoms of
C. perfringens
type A food poisoning and some cases of nonfoodborne gastrointestinal diseases, such as antibiotic-associated diarrhea. In the presence of certain predisposing medical conditions, this toxin can also be absorbed from the intestines to cause enterotoxemic death. CPE action
in vivo
involves intestinal damage, which begins at the villus tips. The cause of this CPE-induced intestinal damage is unknown, but CPE can induce caspase-3-mediated apoptosis in cultured enterocyte-like Caco-2 cells. Therefore, the current study evaluated whether CPE activates caspase-3 in the intestines and, if so, whether this effect is required for the development of intestinal tissue damage or enterotoxemic lethality. Using a mouse ligated small intestinal loop model, CPE was shown to cause intestinal caspase-3 activation in a dose- and time-dependent manner. Most of this caspase-3 activation occurred in epithelial cells shed from villus tips. However, CPE-induced caspase-3 activation occurred after the onset of tissue damage. Furthermore, inhibition of intestinal caspase-3 activity did not affect the onset of intestinal tissue damage. Similarly, inhibition of intestinal caspase-3 activity did not reduce CPE-induced enterotoxemic lethality in these mice. Collectively, these results demonstrate that caspase-3 activation occurs in the CPE-treated intestine but that this effect is not necessary for the development of CPE-induced intestinal tissue damage or enterotoxemic lethality.
Forward Genetic Dissection of Biofilm Development by Fusobacterium nucleatum: Novel Functions of Cell Division Proteins FtsX and EnvC
Authors: Wu Chenggang , Al Mamun Abu Amar Mohamed , Luong Truc Thanh , Hu Bo , Gu Jianhua , Lee Ju Huck , D’Amore Melissa , Das Asis , Ton-That Hung 
Published: April 2018

ABSTRACT

Fusobacterium nucleatum
is a key member of the human oral biofilm. It is also implicated in preterm birth and colorectal cancer. To facilitate basic studies of fusobacterial virulence, we describe here a versatile transposon mutagenesis procedure and a pilot screen for mutants defective in biofilm formation. Out of 10 independent biofilm-defective mutants isolated, the affected genes included the homologs of the
Escherichia coli
cell division proteins FtsX and EnvC, the electron transport protein RnfA, and four proteins with unknown functions. Next, a facile new gene deletion method demonstrated that nonpolar, in-frame deletion of
ftsX
or
envC
produces viable bacteria that are highly filamentous due to defective cell division. Transmission electron and cryo-electron microscopy revealed that the Δ
ftsX
and Δ
envC
mutant cells remain joined with apparent constriction, and scanning electron microscopy (EM) uncovered a smooth cell surface without the microfolds present in wild-type cells. FtsX and EnvC proteins interact with each other as well as a common set of interacting partners, many with unknown function. Last, biofilm development is altered when cell division is blocked by MinC overproduction; however, unlike the phenotypes of Δ
ftsX
and Δ
envC
mutants, a weakly adherent biofilm is formed, and the wild-type rugged cell surface is maintained. Therefore, FtsX and EnvC may perform novel functions in
Fusobacterium
cell biology. This is the first report of an unbiased approach to uncover genetic determinants of fusobacterial biofilm development. It points to an intriguing link among cytokinesis, cell surface dynamics, and biofilm formation, whose molecular underpinnings remain to be elucidated.

IMPORTANCE
Little is known about the virulence mechanisms and associated factors in
F. nucleatum
, due mainly to the lack of convenient genetic tools for this organism. We employed two efficient genetic strategies to identify
F. nucleatum
biofilm-defective mutants, revealing FtsX and EnvC among seven biofilm-associated factors. Electron microscopy established cell division defects of the Δ
ftsX
and Δ
envC
mutants, accompanied with a smooth cell surface, unlike the microfold, rugged appearance of wild-type bacteria. Proteomic studies demonstrated that FtsX and EnvC interact with each other as well as a set of common and unique interacting proteins, many with unknown functions. Importantly, blocking cell division by MinC overproduction led to formation of a weakly adherent biofilm, without alteration of the wild-type cell surface. Thus, this work links cell division and surface dynamics to biofilm development and lays a foundation for future genetic and biochemical investigations of basic cellular processes in this clinically significant pathogen.
Epigenetic Regulation of Tumor Suppressors byHelicobacter pyloriEnhances EBV-Induced Proliferation of Gastric Epithelial Cells
Authors: Pandey Saurabh , Jha Hem Chandra , Shukla Sanket Kumar , Shirley Meghan K. , Robertson Erle S. 
Published: April 2018

ABSTRACTHelicobacter pyloriand Epstein-Barr virus (EBV) are two well-known contributors to cancer and can establish lifelong persistent infection in the host. This leads to chronic inflammation, which also contributes to development of cancer. Association withH. pyloriincreases the risk of gastric carcinoma, and coexistence with EBV enhances proliferation of infected cells. Further,H. pylori-EBV coinfection causes chronic inflammation in pediatric patients. We have established anH. pylori-EBV coinfection model system using human gastric epithelial cells. We showed thatH. pyloriinfection can increase the oncogenic phenotype of EBV-infected cells and that the cytotoxin-associated gene (CagA) protein encoded byH. pyloristimulated EBV-mediated cell proliferation in this coinfection model system. This led to increased expression of DNA methyl transferases (DNMTs), which reprogrammed cellular transcriptional profiles, including those of tumor suppressor genes (TSGs), through hypermethylation. These findings provide new insights into a molecular mechanism whereby cooperativity between two oncogenic agents leads to enhanced oncogenic activity of gastric cancer cells.IMPORTANCEWe have studied the cooperativity betweenH. pyloriand EBV, two known oncogenic agents. This led to an enhanced oncogenic phenotype in gastric epithelial cells. We now demonstrate that EBV-driven epigenetic modifications are enhanced in the presence ofH. pylori, more specifically, in the presence of its CagA secretory antigen. This results in increased proliferation of the infected gastric cells. Our findings now elucidate a molecular mechanism whereby expression of cellular DNA methyl transferases is induced influencing infection by EBV. Hypermethylation of the regulatory genomic regions of tumor suppressor genes results in their silencing. This drastically affects the expression of cell cycle, apoptosis, and DNA repair genes, which dysregulates their associated processes, and promotion of the oncogenic phenotype.
Human Cytomegalovirus Encodes a Novel FLT3 Receptor Ligand Necessary for Hematopoietic Cell Differentiation and Viral Reactivation
Authors: Crawford Lindsey B. , Kim Jung Heon , Collins-McMillen Donna , Lee Byeong-Jae , Landais Igor , Held Christine , Nelson Jay A. , Yurochko Andrew D. , Caposio Patrizia 
Published: April 2018

ABSTRACT

The ability of human cytomegalovirus (HCMV) to reactivate from latent infection of hematopoietic progenitor cells (HPCs) is intimately linked to cellular differentiation. HCMV encodes UL7 that our group has shown is secreted from infected cells and induces angiogenesis. In this study, we show that UL7 is a ligand for Fms-like tyrosine kinase 3 receptor (Flt-3R), a well-known critical factor in HPC differentiation. We observed that UL7 directly binds Flt-3R and induces downstream signaling cascades, including phosphatidylinositol 3-kinase (PI3K)/Akt and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathways. Importantly, we show that UL7 protein induces differentiation of both CD34
+
HPCs and CD14
+
monocytes. Last, we show that an HCMV mutant lacking UL7 fails to reactivate in CD34
+
HPCs
in vitro
as well as in humanized mice. These observations define the first virally encoded differentiation factor with significant implications not only for HCMV reactivation but also for alteration of the hematopoietic compartment in transplant patients.

IMPORTANCE
Human cytomegalovirus (HCMV) remains a significant cause of morbidity and mortality in allogeneic hematopoietic stem cell transplant recipients. CD34
+
hematopoietic progenitor cells (HPCs) represent a critical reservoir of latent HCMV in the transplant population, thereby providing a source of virus for dissemination to visceral organs. HCMV reactivation has been linked to HPC/myeloid cellular differentiation; however, the mechanisms involved in these events are poorly understood at the molecular level. In this study, we show that a viral protein is a ligand for Fms-like tyrosine kinase 3 receptor (Flt-3R) and that the binding of HCMV UL7 to the Flt-3R triggers HPC and monocyte differentiation. Moreover, the loss of UL7 prevents viral reactivation in HPCs
in vitro
as well as in humanized mice. These observations define the first virally encoded differentiation factor with significant implications not only for HCMV reactivation but also for alteration of the hematopoietic compartment in transplant patients.
Clinically Relevant Plasmid-Host Interactions Indicate that Transcriptional and Not Genomic Modifications Ameliorate Fitness Costs of
Klebsiella pneumoniae
Carbapenemase-Carrying Plasmids
Authors: Buckner Michelle M. C. , Saw Howard T. H. , Osagie Rachael N. , McNally Alan , Ricci Vito , Wand Matthew E. , Woodford Neil , Ivens Alasdair , Webber Mark A. , Piddock Laura J. V. 
Published: April 2018

ABSTRACT

The rapid dissemination of antimicrobial resistance (AMR) around the globe is largely due to mobile genetic elements, such as plasmids. They confer resistance to critically important drugs, including extended-spectrum beta-lactams, carbapenems, and colistin. Large, complex resistance plasmids have evolved alongside their host bacteria. However, much of the research on plasmid-host evolution has focused on small, simple laboratory plasmids in laboratory-adapted bacterial hosts. These and other studies have documented mutations in both host and plasmid genes which occur after plasmid introduction to ameliorate fitness costs of plasmid carriage. We describe here the impact of two naturally occurring variants of a large AMR plasmid (pKpQIL) on a globally successful pathogen. In our study, after pKpQIL plasmid introduction, no changes in coding domain sequences were observed in their natural host,
Klebsiella pneumoniae
. However, significant changes in chromosomal and plasmid gene expression may have allowed the bacterium to adapt to the acquisition of the AMR plasmid. We hypothesize that this was sufficient to ameliorate the associated fitness costs of plasmid carriage, as pKpQIL plasmids were maintained without selection pressure. The dogma that removal of selection pressure (e.g., antimicrobial exposure) results in plasmid loss due to bacterial fitness costs is not true for all plasmid/host combinations. We also show that pKpQIL impacted the ability of
K. pneumoniae
to form a biofilm, an important aspect of virulence. This study used highly relevant models to study the interaction between AMR plasmids and pathogens and revealed striking differences from results of studies done on laboratory-adapted plasmids and strains.

IMPORTANCE
Antimicrobial resistance is a serious problem facing society. Many of the genes that confer resistance can be shared between bacteria through mobile genetic elements, such as plasmids. Our work shows that when two clinically relevant AMR plasmids enter their natural host bacteria, there are changes in gene expression, rather than changes to gene coding sequences. These changes in gene expression ameliorate the potential fitness costs of carriage of these AMR plasmids. In line with this, the plasmids were stable within their natural host and were not lost in the absence of selective pressure. We also show that better understanding of the impact of resistance plasmids on fundamental pathogen biology, including biofilm formation, is crucial for fighting drug-resistant infections.
A Genetic Variant Located in miR-146b Promoter Region Is Associated with Prognosis of Gastric Cancer
Authors: Wang Weizhi , Du Mulong , Li Zheng , Zhang Lei , Li Qing , Xu Zhipeng , Li Bowen , Wang Linjun , Li Fengyuan , Zhang Diancai , Xu Hao , Yang Li , Gong Weida , Qiang Fulin , Zhang Zhengdong , Xu Zekuan 
Published: April 2018

Abstract
Background: SNPs in the promoter region of miRNAs have been reported to be associated with cancer prognosis. Our previous study found that miR-146b had a strong correlation with the stage classification of gastric cancer and contributed to tumor progression. The current study was aimed at investigating whether an SNP located in the promoter region of miR-146b could affect the survival rate of gastric cancer.
Methods: Using bioinformatics tools, we identified one SNP (rs1536309) that is located in the miR-146b promoter. We genotyped this SNP site to assess its association with gastric cancer prognosis in 940 cases.
Results: We found that the dominant model of miR-146b rs1536309 was associated with a higher survival rate of gastric cancer. The association remained significant in the subgroup analysis by age (≤60), sex (male), tumor size (≤5 cm), histologic type (diffuse), lymph node metastasis (N0), distant metastasis (M0), and TNM stage (I/II).
Conclusions: Our results suggested that the miR-146b rs1536309 polymorphism may be a potential biomarker for the prognosis of gastric cancer.
Impact: This is the first evidence showing that patients carrying the miR-146b-5p rs1536309 CC/CT genotypes exhibited better survival than those carrying the TT genotype, suggesting the protective effect of the C allele in the prognosis of gastric cancer. Cancer Epidemiol Biomarkers Prev; 27(7); 822–8. ©2018 AACR.
Baseline Tumor Size Is an Independent Prognostic Factor for Overall Survival in Patients with Melanoma Treated with Pembrolizumab
Authors: Joseph Richard W. , Elassaiss-Schaap Jeroen , Kefford Richard , Hwu Wen-Jen , Wolchok Jedd D. , Joshua Anthony M. , Ribas Antoni , Hodi F. Stephen , Hamid Omid , Robert Caroline , Daud Adil , Dronca Roxana , Hersey Peter , Weber Jeffrey S. , Patnaik Amita , de Alwis Dinesh P. , Perrone Andrea , Zhang Jin , Kang S. Peter , Ebbinghaus Scot , Anderson Keaven M. , Gangadhar Tara C. 
Published: April 2018

Abstract
Purpose: The purpose of this study was to assess the association of baseline tumor size (BTS) with other baseline clinical factors and outcomes in pembrolizumab-treated patients with advanced melanoma in KEYNOTE-001 (NCT01295827).
Experimental Design: BTS was quantified by adding the sum of the longest dimensions of all measurable baseline target lesions. BTS as a dichotomous and continuous variable was evaluated with other baseline factors using logistic regression for objective response rate (ORR) and Cox regression for overall survival (OS). Nominal P values with no multiplicity adjustment describe the strength of observed associations.
Results: Per central review by RECIST v1.1, 583 of 655 patients had baseline measurable disease and were included in this post hoc analysis. Median BTS was 10.2 cm (range, 1–89.5). Larger median BTS was associated with Eastern Cooperative Oncology Group performance status 1, elevated lactate dehydrogenase (LDH), stage M1c disease, and liver metastases (with or without any other sites; all P ≤ 0.001). In univariate analyses, BTS below the median was associated with higher ORR (44% vs. 23%; P &lt; 0.001) and improved OS (HR, 0.38; P &lt; 0.001). In multivariate analyses, BTS below the median remained an independent prognostic marker of OS (P &lt; 0.001) but not ORR. In 459 patients with available tumor programmed death ligand 1 (PD-L1) expression, BTS below the median and PD-L1–positive tumors were independently associated with higher ORR and longer OS.
Conclusions: BTS is associated with many other baseline clinical factors but is also independently prognostic of survival in pembrolizumab-treated patients with advanced melanoma. Clin Cancer Res; 24(20); 4960–7. ©2018 AACR.
See related commentary by Warner and Postow, p. 4915
Integrative Kinome Profiling Identifies mTORC1/2 Inhibition as Treatment Strategy in Ovarian Clear Cell Carcinoma
Authors: Caumanns Joseph J. , Berns Katrien , Wisman G. Bea A. , Fehrmann Rudolf S.N. , Tomar Tushar , Klip Harry , Meersma Gert J. , Hijmans E. Marielle , Gennissen Annemiek M.C. , Duiker Evelien W. , Weening Desiree , Itamochi Hiroaki , Kluin Roelof J.C. , Reyners Anna K.L. , Birrer Michael J. , Salvesen Helga B. , Vergote Ignace , van Nieuwenhuysen Els , Brenton James , Braicu E. Ioana , Kupryjanczyk Jolanta , Spiewankiewicz Beata , Mittempergher Lorenza , Bernards René , van der Zee Ate G.J. , de Jong Steven 
Published: April 2018

Abstract
Purpose: Advanced-stage ovarian clear cell carcinoma (OCCC) is unresponsive to conventional platinum-based chemotherapy. Frequent alterations in OCCC include deleterious mutations in the tumor suppressor ARID1A and activating mutations in the PI3K subunit PIK3CA. In this study, we aimed to identify currently unknown mutated kinases in patients with OCCC and test druggability of downstream affected pathways in OCCC models.
Experimental Design: In a large set of patients with OCCC (n = 124), the human kinome (518 kinases) and additional cancer-related genes were sequenced, and copy-number alterations were determined. Genetically characterized OCCC cell lines (n = 17) and OCCC patient–derived xenografts (n = 3) were used for drug testing of ERBB tyrosine kinase inhibitors erlotinib and lapatinib, the PARP inhibitor olaparib, and the mTORC1/2 inhibitor AZD8055.
Results: We identified several putative driver mutations in kinases at low frequency that were not previously annotated in OCCC. Combining mutations and copy-number alterations, 91% of all tumors are affected in the PI3K/AKT/mTOR pathway, the MAPK pathway, or the ERBB family of receptor tyrosine kinases, and 82% in the DNA repair pathway. Strong p-S6 staining in patients with OCCC suggests high mTORC1/2 activity. We consistently found that the majority of OCCC cell lines are especially sensitive to mTORC1/2 inhibition by AZD8055 and not toward drugs targeting ERBB family of receptor tyrosine kinases or DNA repair signaling. We subsequently demonstrated the efficacy of mTORC1/2 inhibition in all our unique OCCC patient–derived xenograft models.
Conclusions: These results propose mTORC1/2 inhibition as an effective treatment strategy in OCCC. Clin Cancer Res; 24(16); 3928–40. ©2018 AACR.
Evaluation of Cancer-Associated DNA Copy Number Events in Colorectal (Advanced) Adenomas
Authors: Carvalho Beatriz , Diosdado Begoña , Terhaar Sive Droste Jochim S. , Bolijn Anne S. , Komor Malgorzata A. , de Wit Meike , Bosch Linda J.W. , van Burink Myrthe , Dekker Evelien , Kuipers Ernst J. , Coupé Veerle M.H. , van Grieken Nicole C.T. , Fijneman Remond J.A. , Meijer Gerrit A. 
Published: April 2018

Abstract
About 5% of colorectal adenomas are estimated to progress to colorectal cancer. However, it is important to identify which adenomas actually carry a high risk of progression, because these serve as intermediate endpoints, for example, in screening programs. In clinical practice, adenomas with a size of ≥10 mm, villous component and/or high-grade dysplasia, called advanced adenomas, are considered high risk, although solid evidence for this classification is lacking. Specific DNA copy number changes are associated with adenoma-to-carcinoma progression. We set out to determine the prevalence of cancer-associated events (CAE) in advanced and nonadvanced adenomas. DNA copy number analysis was performed on archival tissues from three independent series of, in total, 297 adenomas (120 nonadvanced and 177 advanced) using multiplex ligation-dependent probe amplification or low-coverage whole-genome DNA sequencing. Alterations in two or more CAEs were considered to mark adenomas as high risk. Two or more CAEs were overall present in 25% (95% CI, 19.0–31.8) of advanced adenomas; 23% (11/48), 36% (12/33), and 23% (22/96) of the advanced adenomas in series 1, 2, and 3, respectively, and 1.7% (1/58) and 4.8% (3/62) of the nonadvanced adenomas, in series 1 and 2, respectively. The majority of advanced adenomas do not show CAEs, indicating that only a subset of these lesions is to be considered high risk. Nonadvanced adenomas have very low prevalence of CAEs, although those with CAEs should be considered high risk as well. Specific DNA copy number alterations may better reflect the true progression risk than the advanced adenoma phenotype. Cancer Prev Res; 11(7); 403–12. ©2018 AACR.
Revision of the Australian Wet Tropics endemic rainbowfish genus Cairnsichthys (Atheriniformes: Melanotaeniidae), with description of a new species
Authors: HAMMER MICHAEL P. , ALLEN GERALD R. , MARTIN KEITH C. , ADAMS MARK , EBNER BRENDAN C. , RAADIK TARMO A. , UNMACK PETER J. 
Published: April 2018

The freshwater melanotaeniid genus Cairnsichthys is endemic to a relatively small area of specialised habitat within the Wet Tropics bioregion of north-eastern Queensland, Australia. It was previously considered as monotypic, including only a single species, C. rhombosomoides (Nichols & Raven, 1928). The recent discovery of an apparently-isolated population in the Daintree rainforest, approximately 120 km north of the known range extent, prompted a detailed investigation of its taxonomic status using a combined lines of evidence approach. We provide compelling evidence from multiple nuclear genetic markers (52 allozyme loci), mitochondrial DNA sequence data (1141 bp cytochrome b) and morphology (examination of a suite of 38 morphometric and meristic characters) that supports north-south splitting of C. rhombosomoides. Accordingly, we describe the northern population as a distinct species, C. bitaeniatus sp. nov., on the basis of 25 specimens, 34.7–65.6 mm SL. The new species differs morphologically primarily by having a more slender and narrow shape, featuring a flatter, straighter predorsal profile and shorter second dorsal fin base; possession of slightly smaller scales, reflected in higher counts of lateral scales and predorsal scales; typically more vertebrae; and colour differences including a more robust, short black stripe across the upper operculum, a pronounced yellow patch on the anteroventral body and usually a more conspicuous second dark stripe on the lower body, with adult males generally having yellowish compared to reddish fins. We also provide a generic diagnosis for Cairnsichthys and a redescription of C. rhombosomoides. Information on the known distribution, habitats and conservation status of species in the genus is summarised, the new species being of particular concern as a narrow range endemic with specific environmental requirements.