bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genomic Analysis of a Pan-Resistant Isolate of
Klebsiella pneumoniae
, United States 2016
Authors: de Man Tom J. B. , Lutgring Joseph D. , Lonsway David R. , Anderson Karen F. , Kiehlbauch Julia A. , Chen Lei , Walters Maroya Spalding , Sjölund-Karlsson Maria , Rasheed J. Kamile , Kallen Alexander , Halpin Alison Laufer 
Published: April 2018

ABSTRACT

Antimicrobial resistance is a threat to public health globally and leads to an estimated 23,000 deaths annually in the United States alone. Here, we report the genomic characterization of an unusual
Klebsiella pneumoniae
, nonsusceptible to all 26 antibiotics tested, that was isolated from a U.S. patient. The isolate harbored four known beta-lactamase genes, including plasmid-mediated
bla
NDM-1
and
bla
CMY-6
, as well as chromosomal
bla
CTX-M-15
and
bla
SHV-28
, which accounted for resistance to all beta-lactams tested. In addition, sequence analysis identified mechanisms that could explain all other reported nonsusceptibility results, including nonsusceptibility to colistin, tigecycline, and chloramphenicol. Two plasmids, IncA/C2 and IncFIB, were closely related to mobile elements described previously and isolated from Gram-negative bacteria from China, Nepal, India, the United States, and Kenya, suggesting possible origins of the isolate and plasmids. This is one of the first
K. pneumoniae
isolates in the United States to have been reported to the Centers for Disease Control and Prevention (CDC) as nonsusceptible to all drugs tested, including all beta-lactams, colistin, and tigecycline.

IMPORTANCE
Antimicrobial resistance is a major public health threat worldwide. Bacteria that are nonsusceptible or resistant to all antimicrobials available are of major concern to patients and the public because of lack of treatment options and potential for spread. A
Klebsiella pneumoniae
strain that was nonsusceptible to all tested antibiotics was isolated from a U.S. patient. Mechanisms that could explain all observed phenotypic antimicrobial resistance phenotypes, including resistance to colistin and beta-lactams, were identified through whole-genome sequencing. The large variety of resistance determinants identified demonstrates the usefulness of whole-genome sequencing for detecting these genes in an outbreak response. Sequencing of isolates with rare and unusual phenotypes can provide information on how these extremely resistant isolates develop, including whether resistance is acquired on mobile elements or accumulated through chromosomal mutations. Moreover, this provides further insight into not only detecting these highly resistant organisms but also preventing their spread.
Coexistence of Multiple Endemic and Pandemic Lineages of the Rice Blast Pathogen
Authors: Gladieux Pierre , Ravel Sébastien , Rieux Adrien , Cros-Arteil Sandrine , Adreit Henri , Milazzo Joëlle , Thierry Maud , Fournier Elisabeth , Terauchi Ryohei , Tharreau Didier 
Published: April 2018

ABSTRACT

The rice blast fungus
Magnaporthe oryzae
(syn.,
Pyricularia oryzae
) is both a threat to global food security and a model for plant pathology. Molecular pathologists need an accurate understanding of the origins and line of descent of
M. oryzae
populations in order to identify the genetic and functional bases of pathogen adaptation and to guide the development of more effective control strategies. We used a whole-genome sequence analysis of samples from different times and places to infer details about the genetic makeup of
M. oryzae
from a global collection of isolates. Analyses of population structure identified six lineages within
M. oryzae
, including two pandemic on japonica and indica rice, respectively, and four lineages with more restricted distributions. Tip-dating calibration indicated that
M. oryzae
lineages separated about a millennium ago, long after the initial domestication of rice. The major lineage endemic to continental Southeast Asia displayed signatures of sexual recombination and evidence of DNA acquisition from multiple lineages. Tests for weak natural selection revealed that the pandemic spread of clonal lineages entailed an evolutionary “cost,” in terms of the accumulation of deleterious mutations. Our findings reveal the coexistence of multiple endemic and pandemic lineages with contrasting population and genetic characteristics within a widely distributed pathogen.

IMPORTANCE
The rice blast fungus
Magnaporthe oryzae
(syn.,
Pyricularia oryzae
) is a textbook example of a rapidly adapting pathogen, and it is responsible for one of the most damaging diseases of rice. Improvements in our understanding of
Magnaporthe oryzae
’s diversity and evolution are required to guide the development of more effective control strategies. We used genome sequencing data for samples from around the world to infer the evolutionary history of
M. oryzae
. We found that
M. oryzae
diversified about 1,000 years ago, separating into six main lineages: two pandemic on japonica and indica rice, respectively, and four with more restricted distributions. We also found that a lineage endemic to continental Southeast Asia displayed signatures of sexual recombination and the acquisition of genetic material from multiple lineages. This work provides a population-level genomic framework for defining molecular markers for the control of rice blast and investigations of the molecular basis of differences in pathogenicity between
M. oryzae
lineages.
NAction! How Can Neuraminidase-Based Immunity Contribute to Better Influenza Virus Vaccines?
Authors: Krammer Florian , Fouchier Ron A. M. , Eichelberger Maryna C. , Webby Richard J. , Shaw-Saliba Kathryn , Wan Hongquan , Wilson Patrick C. , Compans Richard W. , Skountzou Ioanna , Monto Arnold S. 
Published: April 2018

ABSTRACTNeuraminidase is one of the two surface glycoproteins of influenza A and B viruses. It has enzymatic activity that cleaves terminal sialic acid from glycans, and that activity is essential at several points in the virus life cycle. While neuraminidase is a major target for influenza antivirals, it is largely ignored in vaccine development. Current inactivated influenza virus vaccines might contain neuraminidase, but the antigen quantity and quality are varied and not standardized. While there are data that show a protective role of anti-neuraminidase immunity, many questions remain unanswered. These questions, among others, concern the targeted epitopes or antigenic sites, the potential for antigenic drift, and, connected to that, the breadth of protection, differences in induction of immune responses by vaccination versus infection, mechanisms of protection, the role of mucosal antineuraminidase antibodies, stability, and the immunogenicity of neuraminidase in vaccine formulations. Reagents for analysis of neuraminidase-based immunity are scarce, and assays are not widely used for clinical studies evaluating vaccines. However, efforts to better understand neuraminidase-based immunity have been made recently. A neuraminidase focus group, NAction!, was formed at a Centers of Excellence for Influenza Research and Surveillance meeting at the National Institutes of Health in Bethesda, MD, to promote research that helps to understand neuraminidase-based immunity and how it can contribute to the design of better and broadly protective influenza virus vaccines. Here, we review open questions and knowledge gaps that have been identified by this group and discuss how the gaps can be addressed, with the ultimate goal of designing better influenza virus vaccines.
Chronic kidney disease care models in low- and middle-income countries: a systematic review
Authors: Stanifer John W , Von Isenburg Megan , Chertow Glenn M , Anand Shuchi 
Published: April 2018

IntroductionThe number of persons with chronic kidney disease (CKD) living in low- and middle-income countries (LMIC) is increasing rapidly; yet systems built to care for them have received little attention. In order to inform the development of scalable CKD care models, we conducted a systematic review to characterise existing CKD care models in LMICs.MethodsWe searched PubMed, Embase and WHO Global Health Library databases for published reports of CKD care models from LMICs between January 2000 and 31 October 2017. We used a combination of database-specific medical subject headings and keywords for care models, CKD and LMICs as defined by the World Bank.ResultsOf 3367 retrieved articles, we reviewed the full text of 104 and identified 17 articles describing 16 programmes from 10 countries for inclusion. National efforts (n=4) focused on the prevention of end-stage renal disease through enhanced screening, public awareness campaigns and education for primary care providers. Of the 12 clinical care models, nine focused on persons with CKD and the remaining on persons at risk for CKD; a majority in the first category implemented a multidisciplinary clinic with allied health professionals or primary care providers (rather than nephrologists) in lead roles. Four clinical care models used a randomised control design allowing for assessment of programme effectiveness, but only one was assessed as having low risk for bias; all four showed significant attenuation of kidney function decline in the intervention arms.ConclusionsOverall, very few rigorous CKD care models have been reported from LMICs. While preliminary data indicate that national efforts or clinical CKD care models bolstering primary care are successful in slowing kidney function decline, limited data on regional causes of CKD to inform national campaigns, and on effectiveness and affordability of local programmes represent important challenges to scalability.
The adsorption properties of CHx species on metal modified graphene
Authors: Tang Yanan , Shen Zigang , Chen Weiguang , Zhu Dalei , Chai Huadou , Zhao Mingyu 
Published: April 2018

The adsorption geometries of CH[Formula: see text] species (x = 0, 1, 2, 3 and 4) on the metal embedded graphene (M–graphene) substrates and the change in electronic structure and magnetic property of systems are analyzed using the first-principles calculations. The calculated results show that the doped metal atoms can provide transferred electrons to neighboring carbon atoms at defective site and thus exhibit positive charges, as well as turning the adsorption sensing of M–graphene for detecting CH[Formula: see text] species. Compared with the adsorbed CH3, the adsorption of C, CH and CH2 species exhibit more stability ([Formula: see text]3.0 eV) on M–graphene. Besides, more stable C atom on M–graphene can effectively turn the magnetic property of systems as compared with other species. This result provides a useful reference for fabricating the functional metal–graphene complex as gas sensors and catalytic materials.
Fabrication of absorption gratings with X-ray lithography for X-ray phase contrast imaging
Authors: Wang Bo , Wang Yu-Ting , Yi Fu-Ting , Zhang Tian-Chong , Liu Jing , Zhou Yue 
Published: April 2018

Grating-based X-ray phase contrast imaging is promising especially in the medical area. Two or three gratings are involved in grating-based X-ray phase contrast imaging in which the absorption grating of high-aspect-ratio is the most important device and the fabrication process is a great challenge. The material with large atomic number Z is used to fabricate the absorption grating for excellent absorption of X-ray, and Au is usually used. The fabrication process, which involves X-ray lithography, development and gold electroplating, is described in this paper. The absorption gratings with 4 [Formula: see text]m period and about 100 [Formula: see text]m height are fabricated and the high-aspect-ratio is 50.
CD163 Is Required for Protumoral Activation of Macrophages in Human and Murine Sarcoma
Authors: Shiraishi Daisuke , Fujiwara Yukio , Horlad Hasita , Saito Yoichi , Iriki Toyohisa , Tsuboki Junko , Cheng Pan , Nakagata Naomi , Mizuta Hiroshi , Bekki Hirofumi , Nakashima Yasuharu , Oda Yoshinao , Takeya Motohiro , Komohara Yoshihiro 
Published: April 2018

AbstractRecent findings have shown the significance of CD163-positive macrophages in tumor progression, yet there have been few studies on the function of CD163 in macrophages. Here, we uncover the role of CD163 in macrophage activation using CD163-deficient mice and human samples. We detected CD163 in 62 undifferentiated pleomorphic sarcoma samples, in which a high percentage of CD163-positive macrophages was associated with decreased overall survival and higher histologic grade. We observed macrophage-induced tumor cell proliferation in cocultures of human monocyte-derived macrophages and leiomyosarcoma (TYLMS-1) and myxofibrosarcoma (NMFH-1) cell lines, which was abrogated by silencing of CD163. Tumor development of sarcoma (MCA205 and LM8) cells in CD163-deficient mice was significantly abrogated in comparison with wild-type (WT) mice. Coculture with WT peritoneal macrophages significantly increased proliferation of MCA205 cells but decreased in the presence of CD163-deficient macrophages. Production of IL6 and CXCL2 in CD163-deficient macrophages was suppressed in comparison with WT macrophages, and overexpression of CD163 in CD163-deficient macrophages induced production of IL6 and CXCL2. Silencing of IL6 but not CXCL2 abrogated macrophage-induced proliferation of MCA205 cells. Taken together, our results show that CD163 is involved in protumoral activation of macrophages and subsequent development and progression of tumors in mice and humans.Significance: Macrophage CD163-mediated induction of IL6 promotes tumor development and progression in murine and human malignant tumors. Cancer Res; 78(12); 3255–66. ©2018 AACR.
Renin–Angiotensin System Inhibitors to Mitigate Cancer Treatment–Related Adverse Events
Authors: Pinter Matthias , Kwanten Wilhelmus J. , Jain Rakesh K. 
Published: April 2018

Abstract
Treatment-related side effects are a major clinical problem in cancer treatment. They lead to reduced compliance to therapy as well as increased morbidity and mortality. Well-known are the sequelae of chemotherapy on the heart, especially in childhood cancer survivors. Therefore, measures to mitigate the adverse events of cancer therapy may improve health and quality of life in patients with cancer, both in the short and long term. The renin–angiotensin system (RAS) affects all hallmarks of cancer, and blockage of the RAS is associated with an improved outcome in several cancer types. There is also increasing evidence that inhibition of the RAS might be able to alleviate or even prevent certain types of cancer treatment–related adverse effects. In this review, we summarize the potential of RAS inhibitors to mitigate cancer treatment–related adverse events, with a special emphasis on chemotherapy-induced cardiotoxicity, radiation injury, and arterial hypertension. Clin Cancer Res; 24(16); 3803–12. ©2018 AACR.
Adaptive Resistance to Chemotherapy, A Multi–FAK-torial Linkage
Authors: Taylor Kristin N. , Schlaepfer David D. 
Published: April 2018

Abstract
Oncogenes provide tumor cells with a growth and survival advantage. Directed therapies targeted to oncogenic mutations (such as BRAF V600E) are part of effective late-stage melanoma treatment. However, tumors with BRAF V600E mutations, in approximately 10% of colorectal cancer, are generally treatment-insensitive. Research has identified various “feedback” mechanisms that result in BRAF signal pathway reactivation in response to BRAF inhibition. Herein, we highlight key findings from Chen and colleagues (this issue) showing that integrin-associated focal adhesion kinase (FAK) activation selectively occurs in BRAF V600E-mutant colorectal cancer cells in response to pharmacological BRAF inhibition. FAK activation results in elevated β-catenin protein levels, β-catenin nuclear localization, and increased gene transcription. Small-molecule inhibitors of β-catenin or FAK synergize with vemurafenib BRAF inhibitor to prevent BRAF V600E colorectal cancer cell proliferation in vitro and xenograft tumor growth in mice. This study complements findings linking FAK to β-catenin in intestinal tumorigenesis, resistance to radiotherapy, and cancer stem cell survival. Thus, FAK activation may occur as a frequent tumor cell “adaptive resistance” mechanism. Although FAK (PTK2) is not mutated in most cancers, targeting FAK activity in combinational approaches may limit tumor cell escape mechanisms and enhance durable responses to treatment. Mol Cancer Ther; 17(4); 719–23. ©2018 AACR.
E-Cadherin/ROS1 Inhibitor Synthetic Lethality in Breast Cancer
Authors: Bajrami Ilirjana , Marlow Rebecca , van de Ven Marieke , Brough Rachel , Pemberton Helen N. , Frankum Jessica , Song Feifei , Rafiq Rumana , Konde Asha , Krastev Dragomir B. , Menon Malini , Campbell James , Gulati Aditi , Kumar Rahul , Pettitt Stephen J. , Gurden Mark D. , Cardenosa Marta Llorca , Chong Irene , Gazinska Patrycja , Wallberg Fredrik , Sawyer Elinor J. , Martin Lesley-Ann , Dowsett Mitch , Linardopoulos Spiros , Natrajan Rachael , Ryan Colm J. , Derksen Patrick W.B. , Jonkers Jos , Tutt Andrew N.J. , Ashworth Alan , Lord Christopher J. 
Published: April 2018

AbstractThe cell adhesion glycoprotein E-cadherin (CDH1) is commonly inactivated in breast tumors. Precision medicine approaches that exploit this characteristic are not available. Using perturbation screens in breast tumor cells with CRISPR/Cas9-engineered CDH1 mutations, we identified synthetic lethality between E-cadherin deficiency and inhibition of the tyrosine kinase ROS1. Data from large-scale genetic screens in molecularly diverse breast tumor cell lines established that the E-cadherin/ROS1 synthetic lethality was not only robust in the face of considerable molecular heterogeneity but was also elicited with clinical ROS1 inhibitors, including foretinib and crizotinib. ROS1 inhibitors induced mitotic abnormalities and multinucleation in E-cadherin–defective cells, phenotypes associated with a defect in cytokinesis and aberrant p120 catenin phosphorylation and localization. In vivo, ROS1 inhibitors produced profound antitumor effects in multiple models of E-cadherin–defective breast cancer. These data therefore provide the preclinical rationale for assessing ROS1 inhibitors, such as the licensed drug crizotinib, in appropriately stratified patients.Significance: E-cadherin defects are common in breast cancer but are currently not targeted with a precision medicine approach. Our preclinical data indicate that licensed ROS1 inhibitors, including crizotinib, should be repurposed to target E-cadherin–defective breast cancers, thus providing the rationale for the assessment of these agents in molecularly stratified phase II clinical trials. Cancer Discov; 8(4); 498–515. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 371
Response to ERBB3-Directed Targeted Therapy in NRG1-Rearranged Cancers
Authors: Drilon Alexander , Somwar Romel , Mangatt Biju P. , Edgren Henrik , Desmeules Patrice , Ruusulehto Anja , Smith Roger S. , Delasos Lukas , Vojnic Morana , Plodkowski Andrew J. , Sabari Joshua , Ng Kenneth , Montecalvo Joseph , Chang Jason , Tai Huichun , Lockwood William W. , Martinez Victor , Riely Gregory J. , Rudin Charles M. , Kris Mark G. , Arcila Maria E. , Matheny Christopher , Benayed Ryma , Rekhtman Natasha , Ladanyi Marc , Ganji Gopinath 
Published: April 2018

Abstract
NRG1 rearrangements are oncogenic drivers that are enriched in invasive mucinous adenocarcinomas (IMA) of the lung. The oncoprotein binds ERBB3–ERBB2 heterodimers and activates downstream signaling, supporting a therapeutic paradigm of ERBB3/ERBB2 inhibition. As proof of concept, a durable response was achieved with anti-ERBB3 mAb therapy (GSK2849330) in an exceptional responder with an NRG1-rearranged IMA on a phase I trial (NCT01966445). In contrast, response was not achieved with anti-ERBB2 therapy (afatinib) in four patients with NRG1-rearranged IMA (including the index patient post-GSK2849330). Although in vitro data supported the use of either ERBB3 or ERBB2 inhibition, these clinical results were consistent with more profound antitumor activity and downstream signaling inhibition with anti-ERBB3 versus anti-ERBB2 therapy in an NRG1-rearranged patient-derived xenograft model. Analysis of 8,984 and 17,485 tumors in The Cancer Genome Atlas and MSK-IMPACT datasets, respectively, identified NRG1 rearrangements with novel fusion partners in multiple histologies, including breast, head and neck, renal, lung, ovarian, pancreatic, prostate, and uterine cancers.
Significance: This series highlights the utility of ERBB3 inhibition as a novel treatment paradigm for NRG1-rearranged cancers. In addition, it provides preliminary evidence that ERBB3 inhibition may be more optimal than ERBB2 inhibition. The identification of NRG1 rearrangements across various solid tumors supports a basket trial approach to drug development. Cancer Discov; 8(6); 686–95. ©2018 AACR.
See related commentary by Wilson and Politi, p. 676.
This article is highlighted in the In This Issue feature, p. 663
Long-Term Risk of Cardiovascular Disease in Women Who Have Had Infants With Heart Defects
Authors: Auger Nathalie , Potter Brian J. , Bilodeau-Bertrand Marianne , Paradis Gilles 
Published: April 2018

Background:
The possibility that congenital heart defects signal a familial predisposition to cardiovascular disease has not been investigated. We aimed to determine whether the risk of cardiovascular disorders later in life was higher for women who have had newborns with congenital heart defects.

Methods:
We studied a cohort of 1 084 251 women who had delivered infants between 1989 and 2013 in Quebec, Canada. We identified women whose infants had critical, noncritical, or no heart defects, and tracked the women over time for future hospitalizations for cardiovascular disease, with follow-up extending up to 25 years past pregnancy. We calculated the incidence of cardiovascular hospitalization per 1000 person-years, and used Cox proportional hazards regression to estimate hazard ratios and 95% confidence intervals (CIs) for the association between infant heart defects and risk of maternal cardiovascular hospitalization. Models were adjusted for age, parity, preeclampsia, comorbidity, material deprivation, and time period.

Results:
Women whose infants had heart defects had a higher overall incidence of cardiovascular hospitalization. There were 3.38 cardiovascular hospitalizations per 1000 person-years for those with critical defects (95% CI, 2.67–4.27), 3.19 for noncritical defects (95% CI, 2.96–3.45), and 2.42 for no heart defects (95% CI, 2.39–2.44). In comparison with no heart defects, women whose infants had critical defects had a hazard ratio of 1.43 (95% CI, 1.13–1.82) for any cardiovascular hospitalization, and women whose infants had noncritical defects had a hazard ratio of 1.24 (95% CI, 1.15–1.34), in adjusted models. Risks of specific causes of cardiovascular hospitalization, including myocardial infarction, heart failure, and other atherosclerotic disorders, were also greater for mothers of infants with congenital heart defects than with no defects.

Conclusions:
Women whose infants have congenital heart defects have a greater risk of cardiovascular hospitalization later in life. Congenital heart defects in offspring may be an early marker of predisposition to cardiovascular disease.