bluuebunny/crossref_metadata_2025_split huggingface dataset:
HLA‐G 3′ untranslated region polymorphisms influence the susceptibility for human papillomavirus infection
Authors: Xu H.‐H. , Shi W.‐W. , Lin A. , Yan W.‐H. 
Published: April 2014

AbstractHuman leukocyte antigen (HLA)‐G molecule acts as a potential factor for the regulation of immune responses and its expression in virus‐infected cells may enable them to escape immunosurveillance. Besides its polymorphic promoter region, the 3′ untranslated region (UTR) seems to play an important role in regulating HLA‐G expression. In this study, we investigated the influence of HLA‐G 14 bp (rs66554220) and +3142 (rs1063320) polymorphisms in 179 women with active human papillomavirus (HPV) infection and 143 age‐matched, unrelated, HPV‐negative, normal Chinese Han population. Our findings showed that frequency of the allele +3142 C [31.3% vs 44.4%, odds ratio (OR) = 0.57, Pc < 0.01] and the genotype +3142 CC (10.6% vs 21.7%, OR = 0.43, Pc = 0.012) was significantly decreased in HPV infected patients compared with normal controls. Furthermore, the haplotype −14 bp/C was associated with a reduced risk for HPV infection (OR = 0.57, Pc = 0.001). Our findings also showed that HLA‐G homozygous +14 bp/+14 bp genotype was significantly associated with an increased risk for HPV18 infection (OR = 12.95, P < 0.01), whereas HLA‐G heterozygous +14 bp/−14 bp genotype increased risk for HPV58 (OR = 5.55, P < 0.05). Furthermore, frequency of the haplotype +14 bp/G was significantly increased in HPV18 infected patients (60.0% vs 27.3%, OR = 4.00, Pc < 0.05). Taken together, our results supported a role of the HLA‐G 3′ UTR polymorphisms as a susceptible factor for the active HPV infection, and suggested a possible interference of the HLA‐G molecule in the response to virus infection.
Triosephosphate Isomerase Is Dispensable
In Vitro
yet Essential for Mycobacterium tuberculosis To Establish Infection
Authors: Trujillo Carolina , Blumenthal Antje , Marrero Joeli , Rhee Kyu Y. , Schnappinger Dirk , Ehrt Sabine 
Published: April 2014

ABSTRACT

Triosephosphate isomerase (TPI) catalyzes the interconversion of dihydroxyacetone phosphate (DHAP) and glyceraldehyde-3-phosphate (G3P). This reaction is required for glycolysis and gluconeogenesis, and
tpi
has been predicted to be essential for growth of
Mycobacterium tuberculosis
. However, when studying a conditionally regulated
tpi
knockdown mutant, we noticed that depletion of TPI reduced growth of
M. tuberculosis
in media containing a single carbon source but not in media that contained both a glycolytic and a gluconeogenic carbon source. We used such two-carbon-source media to isolate a
tpi
deletion (Δ
tpi
) mutant. The Δ
tpi
mutant did not survive with single carbon substrates but grew like wild-type (WT)
M. tuberculosis
in the presence of both a glycolytic and a gluconeogenic carbon source.
13
C metabolite tracing revealed the accumulation of TPI substrates in Δ
tpi
and the absence of alternative triosephosphate isomerases and metabolic bypass reactions, which confirmed the requirement of TPI for glycolysis and gluconeogenesis in
M. tuberculosis
. The Δ
tpi
strain was furthermore severely attenuated in the mouse model of tuberculosis, suggesting that
M. tuberculosis
cannot simultaneously access sufficient quantities of glycolytic and gluconeogenic carbon substrates to establish infection in mice.

IMPORTANCE
The importance of central carbon metabolism for the pathogenesis of
M. tuberculosis
has recently been recognized, but the consequences of depleting specific metabolic enzymes remain to be identified for many enzymes. We investigated triosephosphate isomerase (TPI) because it is central to both glycolysis and gluconeogenesis and had been predicted to be essential for growth of
M. tuberculosis
. This work identified metabolic conditions that make TPI dispensable for
M. tuberculosis
growth in culture and proved that
M. tuberculosis
relies on a single TPI enzyme and has no metabolic bypass for the TPI-dependent interconversion of dihydroxyacetone phosphate and glyceraldehyde-3-phosphate in glycolysis and gluconeogenesis. Finally, we demonstrate that TPI is essential for growth of the pathogen in mouse lungs.
Revealing the Bacterial Butyrate Synthesis Pathways by Analyzing (Meta)genomic Data
Authors: Vital Marius , Howe Adina Chuang , Tiedje James M. 
Published: April 2014

ABSTRACTButyrate-producing bacteria have recently gained attention, since they are important for a healthy colon and when altered contribute to emerging diseases, such as ulcerative colitis and type II diabetes. This guild is polyphyletic and cannot be accurately detected by 16S rRNA gene sequencing. Consequently, approaches targeting the terminal genes of the main butyrate-producing pathway have been developed. However, since additional pathways exist and alternative, newly recognized enzymes catalyzing the terminal reaction have been described, previous investigations are often incomplete. We undertook a broad analysis of butyrate-producing pathways and individual genes by screening 3,184 sequenced bacterial genomes from the Integrated Microbial Genome database. Genomes of 225 bacteria with a potential to produce butyrate were identified, including many previously unknown candidates. The majority of candidates belong to distinct families within theFirmicutes, but members of nine other phyla, especially fromActinobacteria,Bacteroidetes,Fusobacteria,Proteobacteria,Spirochaetes, andThermotogae, were also identified as potential butyrate producers. The established gene catalogue (3,055 entries) was used to screen for butyrate synthesis pathways in 15 metagenomes derived from stool samples of healthy individuals provided by the HMP (Human Microbiome Project) consortium. A high percentage of total genomes exhibited a butyrate-producing pathway (mean, 19.1%; range, 3.2% to 39.4%), where the acetyl-coenzyme A (CoA) pathway was the most prevalent (mean, 79.7% of all pathways), followed by the lysine pathway (mean, 11.2%). Diversity analysis for the acetyl-CoA pathway showed that the same few firmicute groups associated with severalLachnospiraceaeandRuminococcaceaewere dominating in most individuals, whereas the other pathways were associated primarily withBacteroidetes.IMPORTANCEMicrobiome research has revealed new, important roles of our gut microbiota for maintaining health, but an understanding of effects of specific microbial functions on the host is in its infancy, partly because in-depth functional microbial analyses are rare and publicly available databases are often incomplete/misannotated. In this study, we focused on production of butyrate, the main energy source for colonocytes, which plays a critical role in health and disease. We have provided a complete database of genes from major known butyrate-producing pathways, using in-depth genomic analysis of publicly available genomes, filling an important gap to accurately assess the butyrate-producing potential of complex microbial communities from “-omics”-derived data. Furthermore, a reference data set containing the abundance and diversity of butyrate synthesis pathways from the healthy gut microbiota was established through a metagenomics-based assessment. This study will help in understanding the role of butyrate producers in health and disease and may assist the development of treatments for functional dysbiosis.
Cryptococcus
at Work: Gene Expression during Human Infection
Authors: Upadhya Rajendra , Donlin Maureen J. , Lodge Jennifer K. 
Published: April 2014

ABSTRACT

Meningitis is a frequent manifestation of infection due to
Cryptococcus neoformans
and a major cause of increased morbidity in patients with AIDS. Numerous
in vitro
gene expression and genetic studies of the fungus have predicted a myriad of genes, pathways, and biological processes that may be critical for pathogenesis, and many studies using animal models have supported the role of these processes during infection. However, the relevance of these hypotheses based on
in vitro
and animal models has often been questioned. A recent study by Chen et al. [Y. Chen, D. L. Toffaletti, J. L. Tenor, A. P. Litvintseva, C. Fang, T. G. Mitchell, T. R. McDonald, K. Nielsen, D. R. Boulware, T. Bicanic, and J. R. Perfect, mBio 5(1):e01087-13, 2014] represents an important step in understanding the cryptococcal response during human infection.
Immunoglobulin E and Allergy: Antibodies in Immune Inflammation and Treatment
Authors: Karagiannis Sophia N. , Karagiannis Panagiotis , Josephs Debra H. , Saul Louise , Gilbert Amy E. , Upton Nadine , Gould Hannah J. 
Published: April 2014

ABSTRACTThe pathogenic role of immunoglobulin E (IgE) antibodies in triggering and maintaining allergic inflammation in response to allergens is due to the binding of multivalent allergens to allergen-specific IgEs on sensitized effector cells. These interactions trigger effector cell activation, resulting in release of potent inflammatory mediators, recruitment of inflammatory cells, antigen presentation, and production of allergen-specific antibody responses. Since its discovery in the 1960s, the central role of IgE in allergic disease has been intensively studied, placing IgE and its functions at the heart of therapeutic efforts for the treatment of allergies. Here, we provide an overview of the nature, roles, and significance of IgE antibodies in allergic diseases, infections, and inflammation and the utility of antibodies as therapies. We place special emphasis on allergen-IgE-Fcε receptor complexes in the context of allergic and inflammatory diseases and describe strategies, including monoclonal antibodies, aimed at interrupting these complexes. Of clinical significance, one antibody, omalizumab, is presently in clinical use and works by preventing formation of IgE-Fcε receptor interactions. Active immunotherapy approaches with allergens and allergen derivatives have also demonstrated clinical benefits for patients with allergic diseases. These treatments are strongly associated with serum increases of IgE-neutralizing antibodies and feature a notable redirection of humoral responses towards production of antibodies of the IgG4 subclass in patients receiving immunotherapies. Lastly, we provide a new perspective on the rise of recombinant antibodies of the IgE class recognizing tumor-associated antigens, and we discuss the potential utility of tumor antigen-specific IgE antibodies to direct potent IgE-driven immune responses against tumors.
General Practice Locum Improvement Tool
Authors: Weatherburn Christopher , Hasan Shawkat 
Published: April 2014

AbstractAn improvement culture is required in the NHS. Staff members who move from one place of work to another are often best placed to see alternative methods of working that at times are more efficient – locum general practitioners (GPs) tend to be in this category. A tool was developed specifically to obtain quality improvement suggestions to the general practice from the locum GP and vice versa in a time efficient manner. A pilot study was performed in one general practice in Tayside (Grove Health Centre) in December 2013 to assess if this was possible. During this month a general practice partner provided feedback to the locum GP by completing a drop down tick box survey while reviewing three cases dealt with by the locum. The locum GP was emailed after their session with a one question survey enquiring about improvement suggestions for that practice. Five different locum GPs provided clinical cover during the month studied – of these, one opted out from the study. The other four locums performed their clinical session and completed the survey. Feedback from the practice to locums included specific clinical guidance, suggestions for improving documentation, and ways to optimise referrals; of note, unique feedback was given to each locum and this was generated using this tool. Themes from the locum suggestions to the practice included more physical resources (such as cameras in each room), different ways of handling prescriptions, and a suggestion about identifying complex patients. As a direct result of this pilot a locum box has been implemented in this practice and plans are to rerun this tool periodically. The authors would recommend utilising this tool periodically in other general practices as it has the potential to identify improvement suggestions unique for that particular practice.
An Inference Engine for Estimating Outside States of Clinical Test Items
Authors: Sakata Masato , Yücel Zeynep , Shinozawa Kazuhiko , Hagita Norihiro , Imai Michita , Furutani Michiko , Matsuoka Rumiko 
Published: April 2014

Common periodical health check-ups include several clinical test items with affordable cost. However, these standard tests do not directly indicate signs of most lifestyle diseases. In order to detect such diseases, a number of additional specific clinical tests are required, which increase the cost of the health check-up. This study aims to enrich our understanding of the common health check-ups and proposes a way to estimate the signs of several lifestyle diseases based on the standard tests in common examinations without performing any additional specific tests. In this manner, we enable a diagnostic process, where the physician may prefer to perform or avoid a costly test according to the estimation carried out through a set of common affordable tests. To that end, the relation between standard and specific test results is modeled with a multivariate kernel density estimate. The condition of the patient regarding a specific test is assessed following a Bayesian framework. Our results indicate that the proposed method achieves an overall estimation accuracy of 84%. In addition, an outstanding estimation accuracy is achieved for a subset of high-cost tests. Moreover, comparison with standard artificial intelligence methods suggests that our algorithm outperforms the conventional methods.Our contributions are as follows: (i) promotion of affordable health check-ups, (ii) high estimation accuracy in certain tests, (iii) generalization capability due to ease of implementation on different platforms and institutions, (iv) flexibility to apply to various tests and potential to improve early detection rates.
Treating Postlaparoscopic Surgery Shoulder Pain with Acupuncture
Authors: Kreindler Gur , Attias Samuel , Kreindler Anna , Hen Haim , Haj Bassel , Matter Ibrahim , Ben-Arye Eran , Schiff Elad 
Published: April 2014

Objective. The purpose of this study was to examine the effect of acupuncture on postlaparoscopic shoulder pain (PLSP) which is a common side effect in patients undergoing abdominal laparoscopic surgery. Methods. Patients with moderate to severe PLSP in spite of analgesic treatment, which were referred by the medical staff to the Complementary‐Integrative Surgery Service (CISS) at our institution, were provided with acupuncture treatment. The severity of PLSP and of general pain was assessed using a Visual Analogue Scale (VAS) from 0 to 10. Pain assessment was conducted prior to and two hours following acupuncture treatment. Acupuncture treatment was individualized based on traditional Chinese medicine diagnosis. Results. A total of 25 patients were evaluated during a 14‐month period, from March 2011 to May 2012. A significant reduction in PLSP (mean reduction of 6.4 ± 2.3  P < 0.0001) and general pain (mean reduction 6.4 ± 2.1  P < 0.0001) were observed, and no significant side effects were reported. Conclusion. Individualized acupuncture treatments according to traditional Chinese medicine principles may improve postlaparoscopic shoulder pain and general pain when used in conjunction with conventional therapy. The primary findings of this study warrant verification in controlled studies.
G Protein–Coupled Receptor Kinase GRK5 Phosphorylates Moesin and Regulates Metastasis in Prostate Cancer
Authors: Chakraborty Prabir Kumar , Zhang Yushan , Coomes Alexandra S. , Kim Wan-Ju , Stupay Rachel , Lynch Lauren D. , Atkinson Tamieka , Kim Jae I. , Nie Zhongzhen , Daaka Yehia 
Published: April 2014

Abstract
G protein–coupled receptor kinases (GRK) regulate diverse cellular functions ranging from metabolism to growth and locomotion. Here, we report an important contributory role for GRK5 in human prostate cancer. Inhibition of GRK5 kinase activity attenuated the migration and invasion of prostate cancer cells and, concordantly, increased cell attachment and focal adhesion formation. Mass spectrometric analysis of the phosphoproteome revealed the cytoskeletal-membrane attachment protein moesin as a putative GRK5 substrate. GRK5 regulated the subcellular distribution of moesin and colocalized with moesin at the cell periphery. We identified amino acid T66 of moesin as a principal GRK5 phosphorylation site and showed that enforcing the expression of a T66-mutated moesin reduced cell spreading. In a xenograft model of human prostate cancer, GRK5 silencing reduced tumor growth, invasion, and metastasis. Taken together, our results established GRK5 as a key contributor to the growth and metastasis of prostate cancer. Cancer Res; 74(13); 3489–500. ©2014 AACR.
NADPH Oxidase NOX4 Supports Renal Tumorigenesis by Promoting the Expression and Nuclear Accumulation of HIF2α
Authors: Gregg Jennifer L. , Turner Robert M. , Chang Guimin , Joshi Disha , Zhan Ye , Chen Li , Maranchie Jodi K. 
Published: April 2014

Abstract
Most sporadically occurring renal tumors include a functional loss of the tumor suppressor von Hippel Lindau (VHL). Development of VHL-deficient renal cell carcinoma (RCC) relies upon activation of the hypoxia-inducible factor-2α (HIF2α), a master transcriptional regulator of genes that drive diverse processes, including angiogenesis, proliferation, and anaerobic metabolism. In determining the critical functions for HIF2α expression in RCC cells, the NADPH oxidase NOX4 has been identified, but the pathogenic contributions of NOX4 to RCC have not been evaluated directly. Here, we report that NOX4 silencing in VHL-deficient RCC cells abrogates cell branching, invasion, colony formation, and growth in a murine xenograft model RCC. These alterations were phenocopied by treatment of the superoxide scavenger, TEMPOL, or by overexpression of manganese superoxide dismutase or catalase. Notably, NOX4 silencing or superoxide scavenging was sufficient to block nuclear accumulation of HIF2α in RCC cells. Our results offer direct evidence that NOX4 is critical for renal tumorigenesis and they show how NOX4 suppression and VHL re-expression in VHL-deficient RCC cells are genetically synonymous, supporting development of therapeutic regimens aimed at NOX4 blockade. Cancer Res; 74(13); 3501–11. ©2014 AACR.
Genetic and Pharmacological Strategies to Refunctionalize the von Hippel Lindau R167Q Mutant Protein
Authors: Ding Zhiyong , German Peter , Bai Shanshan , Reddy A. Srinivas , Liu Xian-De , Sun Mianen , Zhou Lijun , Chen Xiaohua , Zhao Xiaobei , Wu Chengbiao , Zhang Shuxing , Mills Gordon B. , Jonasch Eric 
Published: April 2014

Abstract
Aberrant von Hippel Lindau (VHL) protein function is the underlying driver of VHL-related diseases, including both sporadic and inherited clear cell renal cell carcinoma (ccRCC). About one third of VHL mutations are missense point mutations, with R167Q being the most common VHL point mutation in hereditary VHL disease. Although it has been studied extensively, the ability of VHL-R167Q to downregulate hypoxia-inducible factor 2α (HIF2α) is still controversial. In addition, the manner in which the mutation contributes to tumorigenesis is not fully understood. No therapeutic approach is available to target VHL-R167Q and similar missense point mutations. We analyzed VHL-R167Q proteostasis and function at normoxia, at hypoxia with different oxygen pressure, and in a xenograft mouse model. We showed that the protein levels of VHL-R167Q dictate its ability to downregulate HIF2α and suppress tumor growth. Strikingly, the proteasome inhibitors bortezomib and carfilzomib, which are currently in clinical use, stabilize VHL-R167Q and increase its ability to downregulate HIF2α. VHL-R167Q binds elongin C and elongin B with considerably less avidity than wild-type VHL does but retains residual capacity to generate a VHL-elongin C-elongin B complex, downregulate HIF2α, and suppress tumorigenesis, which could be rescued by increase of VHL-R167Q levels. Finally, we used in silico approaches and identified other missense VHL mutants in addition to VHL-R167Q that might be rescued by similar strategies. Thus, our studies revealed detailed information describing how VHL-R167Q contributes to tumorigenesis and identified a potential targeted therapy for ccRCC and other VHL-related disease in patients carrying VHL-R167Q or similar missense mutations. Cancer Res; 74(11); 3127–36. ©2014 AACR.
Colorectal Cancer Cell Lines Are Representative Models of the Main Molecular Subtypes of Primary Cancer
Authors: Mouradov Dmitri , Sloggett Clare , Jorissen Robert N. , Love Christopher G. , Li Shan , Burgess Antony W. , Arango Diego , Strausberg Robert L. , Buchanan Daniel , Wormald Samuel , O'Connor Liam , Wilding Jennifer L. , Bicknell David , Tomlinson Ian P.M. , Bodmer Walter F. , Mariadason John M. , Sieber Oliver M. 
Published: April 2014

Abstract
Human colorectal cancer cell lines are used widely to investigate tumor biology, experimental therapy, and biomarkers. However, to what extent these established cell lines represent and maintain the genetic diversity of primary cancers is uncertain. In this study, we profiled 70 colorectal cancer cell lines for mutations and DNA copy number by whole-exome sequencing and SNP microarray analyses, respectively. Gene expression was defined using RNA-Seq. Cell line data were compared with those published for primary colorectal cancers in The Cancer Genome Atlas. Notably, we found that exome mutation and DNA copy-number spectra in colorectal cancer cell lines closely resembled those seen in primary colorectal tumors. Similarities included the presence of two hypermutation phenotypes, as defined by signatures for defective DNA mismatch repair and DNA polymerase ϵ proofreading deficiency, along with concordant mutation profiles in the broadly altered WNT, MAPK, PI3K, TGFβ, and p53 pathways. Furthermore, we documented mutations enriched in genes involved in chromatin remodeling (ARID1A, CHD6, and SRCAP) and histone methylation or acetylation (ASH1L, EP300, EP400, MLL2, MLL3, PRDM2, and TRRAP). Chromosomal instability was prevalent in nonhypermutated cases, with similar patterns of chromosomal gains and losses. Although paired cell lines derived from the same tumor exhibited considerable mutation and DNA copy-number differences, in silico simulations suggest that these differences mainly reflected a preexisting heterogeneity in the tumor cells. In conclusion, our results establish that human colorectal cancer lines are representative of the main subtypes of primary tumors at the genomic level, further validating their utility as tools to investigate colorectal cancer biology and drug responses. Cancer Res; 74(12); 3238–47. ©2014 AACR.
New Strategies in Ewing Sarcoma: Lost in Translation?
Authors: Arnaldez Fernanda I. , Helman Lee J. 
Published: April 2014

Abstract
Ewing sarcoma is the second most common pediatric malignant bone tumor. Aggressive multimodality therapy has led to an improvement in outcomes, particularly in patients with localized disease. However, therapy-related toxicities are not trivial, and the prognosis for patients with relapsed and/or metastatic disease continues to be poor. In this article, we outline some of the promising therapies that have the potential to change the Ewing sarcoma therapeutic paradigm in the not-too-distant future: insulin-like growth factor receptor inhibitors, targeting of the fusion protein, epigenetic manipulation, PARP inhibitors, and immunotherapy. Clin Cancer Res; 20(12); 3050–6. ©2014 AACR.