bluuebunny/crossref_metadata_2025 huggingface dataset:
A distinct serum metabolic signature of distant metastatic papillary thyroid carcinoma
Authors: Shen Chen‐Tian , Zhang Yinan , Liu Yu‐Min , Yin Shan , Zhang Xin‐Yun , Wei Wei‐Jun , Sun Zhen‐Kui , Song Hong‐Jun , Qiu Zhong‐Ling , Wang Cong‐Rong , Luo Quan‐Yong
Published: July 2017

Background

Although the incidence rate for thyroid cancer seems to have begun stabilizing in recent years, an increased rate of advanced stage of this disease has been reported. Additionally, distant metastasis is one of the most important prognostic factors of patients with papillary thyroid carcinoma (PTC). Unfortunately, the underlying mechanisms of distant metastasis, as well as cell status like metabolism changes in distant metastatic tumours have not been clearly elucidated.

Objective

To identify serum metabolic signature of distant metastatic PTC.

Design, patients and measurements

In this study, gas chromatography‐time‐of‐flight mass spectrometry (GC‐TOF‐MS) was used to analyse the serum from 77 patients diagnosed with PTC (37 in distant metastasis group and 40 in ablation group). Principal component analysis (PCA) and orthogonal partial least‐squares‐discriminant analysis (OPLS‐DA) scores plots were used to analyse the data.

Results

Principal component analysis and OPLS‐DA analyses demonstrated an evident trend of separation between 40 serum samples from the ablation group and 37 samples from distant metastasis group. A total of 31 metabolites were identified, which are related to amino acid, lipid, glucose, vitamin metabolism and diet/gut microbiota interaction. Pathway analysis showed “alanine, aspartate and glutamate metabolism” and “inositol phosphate metabolism” were the most relevant pathways.

Conclusion

Serum metabolomics profiling could significantly discriminate papillary thyroid cancer patients according to distant metastasis. Potential metabolic aberration in distant metastatic PTC could be involved in different biological behaviours of tumour cells including proliferation, invasion/migration and immune escape. Diet/gut microbiota‐produced metabolites could play an important role in these effects. This work may provide new clues to find the underlying mechanisms regarding the distant metastasis of PTC as well as potential adjuvant therapy targets.
Matches and mismatches between conservation investments and biodiversity values in the European Union
Authors: Sánchez‐Fernández David , Abellán Pedro , Aragón Pedro , Varela Sara , Cabeza Mar
Published: July 2017

Recently, the European Commission adopted a new strategy to halt the loss of biodiversity. Member states are expected to favor a more effective collection and redistribution of European Union (EU) funds under the current Multiannual Financial Framework for 2014–2020. Because of the large spatial variation in the distribution of biodiversity and conservation needs at the continental scale, EU instruments should ensure that countries with higher biodiversity values get more funds and resources for the conservation than other countries. Using linear regressions, we assessed the association between conservation investments and biodiversity values across member states, accounting for a variety of conservation investment indicators, taxonomic groups (including groups of plants, vertebrates, and invertebrates), and indicators of biodiversity value. In general, we found clear overall associations between conservation investments and biodiversity variables. However, some countries received more or less investment than would be expected based on biodiversity values in those countries. We also found that the extensive use of birds as unique indicators of conservation effectiveness may lead to biased decisions. Our results can inform future decisions regarding funding allocation and thus improve distribution of EU conservation funds.
Smoking is a risk factor for pulmonary metastasis in colorectal cancer
Authors: Yahagi M. , Tsuruta M. , Hasegawa H. , Okabayashi K. , Toyoda N. , Iwama N. , Morita S. , Kitagawa Y.
Published: July 2017

Aim

The hepatic microenvironment, which may include chronic inflammation and fibrosis, is considered to contribute to the pathogenesis of liver metastases of colorectal cancer. A similar mechanism is anticipated for pulmonary metastases, although no reports are available. Smoking causes pulmonary inflammation and fibrosis. Thus, we hypothesized that smokers would be especially affected by pulmonary metastases of colorectal cancer. In this study, we attempted to clarify the impact of smoking on pulmonary metastasis of colorectal cancer.

Method

Between September 2005 and December 2010 we reviewed 567 patients with pathological Stage I, II or III colorectal cancer, whose clinicopathological background included a preoperative smoking history, pack‐year history from medical records. Univariate and multivariate analyses using the Cox proportional hazard model were performed to determine the independent prognostic factors for pulmonary metastasis‐free survival.

Results

Pulmonary metastases occurred in 39 (6.9%) patients. The smoking histories revealed 355 never smokers, 119 former smokers and 93 current smokers among the subjects. Multivariate analysis revealed that being a current smoker (hazard ratio = 2.72, 95% CI 1.18–6.25; P = 0.02) was an independent risk factor for pulmonary metastases.

Conclusion

Smoking may be a risk factor for pulmonary metastasis of colorectal cancer. Cessation of smoking should be recommended to prevent pulmonary metastasis, although further basic and clinical studies are required.
Medicaid expansion and chronic obstructive pulmonary disease among low‐income adults in the United States
Authors: Tumin Dmitry , Jackson Edwin J. , Hayes Don
Published: July 2017

Introduction

Chronic obstructive pulmonary disease (COPD) is common but often underdiagnosed in the United States (US). Public health insurance coverage expansion may increase the prevalence of diagnosed COPD due to improved access to care and diagnosis.

Objective

We sought to determine the effects of Medicaid expansion on the prevalence of diagnosed COPD among low‐income US adults.

Methods

The 2011‐2015 Behavioral Risk Factor Surveillance System survey data were used to identify adults with annual household income <$50 000. The outcome was self‐report of being diagnosed with COPD by a health‐care provider. Difference‐in‐difference logistic regression contrasted the influence of period (pre‐expansion, 2011‐2013, vs post‐expansion, 2014‐2015) between states participating and opting out of Medicaid expansion.

Results

Data on 521 622 respondents were analysed. The prevalence of diagnosed COPD was 7% in Medicaid expansion states and 8% in non‐participating states. In participating states, lack of health insurance among low‐income adults decreased from 32% to 21% after Medicaid expansion (P < .001), but the prevalence of diagnosed COPD was unchanged. Multivariable logistic regression confirmed that residents of participating states surveyed after Medicaid expansion were no more likely to report diagnosed COPD than residents of these states surveyed before Medicaid expansion (OR = 1.03; 95% CI: 0.97, 1.10; P = .276).

Conclusions

Notwithstanding increased health insurance coverage among low‐income adults after Medicaid expansion, this policy did not increase the prevalence of diagnosed COPD. Access to primary care among new Medicaid enrollees and practices of diagnosing COPD in this setting should be evaluated to reduce the extent of undiagnosed COPD in socioeconomically disadvantaged groups.
Relationship between driver gene mutations, their relative protein expressions and survival in non‐small cell lung carcinoma in Macao
Authors: Chan Kin Iong , Vong Hong Ting , Sin Lai Fong , Yip Yuk Ching , Zhong Xue Yun , Wen Jian Ming
Published: July 2017

Objectives

We report the status of most common gene mutations in non‐small cell lung carcinoma (NSCLC) in Macao, and explore the relationship between each gene mutation and clinicopathologic features and survival.

Methods

EGFR, KRAS and BRAF mutations were detected by PCR in 122 cases of NSCLC. ALK translocation and MET amplification were detected by fluorescence in situ hybridization (FISH). MET and thyroid transcription factor (TTF‐1) were investigated by immunohistochemistry. Clinical data were collected for analyzing their correlation with the gene mutations.

Results

The mutation of EGFR, KRAS and BRAF was detected in 48 (39.3%), 13 (10.7%) and 3 (2.5%) of 122 cases of NSCLC, respectively. ALK translocation and MET amplification were detected in 7 (5.7%) and 3 cases (2.5%). The rate of EGFR mutation was significantly higher in female and non‐smoker patients. In TTF‐1 positive cases EGFR mutation was more frequent. Age of the patients over 62‐year old was correlated with KRAS mutations. The concordance between ALK IHC and FISH was 58.3%. The MET protein in the cases with MET amplification was 100% positive. The survival was lower in the patients with positive MET protein than those with negative. MET protein was an independent prognostic factor for NSCLC.

Conclusions

EGFR mutation occurred frequently in the female never smoke patients with NSCLC. KRAS mutation was more common in old patients. Negative MET protein expression could be used as a negative predictive marker of MET amplification. MET protein expression was an independent prognostic factor for NSCLC.
Sputum bacteriology and clinical response to antibiotics in moderate exacerbation of chronic obstructive pulmonary disease
Authors: Ra Seung Won , Kwon Yong Soo , Yoon Sung Ho , Jung Chi Young , Kim Jusang , Choi Hye Sook , Sheen Seung Soo , Hwang Hun Gyu , Lee Ji‐Hyun , Kim Tae‐Hyung
Published: July 2017

Background

Presence of purulent sputum during an acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is considered sufficient indication for starting empirical antibiotics. We investigated the relationship between detection of potentially pathogenic bacteria (PPB) using sputum culture or polymerase chain reaction (PCR) and clinical response and sought the risk factors for PPB growth.

Methods

In 342 outpatients with AECOPD, we compared detection rates of H. influenzae (HI) and S. pneumoniae (SP) using conventional sputum culture versus PCR. The utility of either technique to predict clinical cure or failure after effective antibiotics was assessed. The factors predicting positive sputum cultures were evaluated using logistic regression.

Results

Using sputum culture, 132 PPB were detected. The predominant bacteria were HI (40.9%) and SP (19.7%). Detection of HI or SP in sputum was higher using PCR than culture growth (60.8% vs 18.6%; P < .001). Clinical response was not affected by the results of either technique. Independent risk factors for PPB isolation were Gram‐negative bacteria on sputum smear (OR 15.78, 95% CI 6.38‐39.06; P < .001), sputum purulence (OR 2.31, 95% CI, 1.05‐5.11; P = .04), body temperature (OR 0.16, 95% CI 0.05‐0.54; P = .003), albumin level (OR 0.29, 95% CI 0.09‐0.88; P = .03) and dyspnea grade (OR 0.51, 95% CI 0.27‐0.96; P = .04).

Conclusions

Neither culture growth nor PCR positivity for HI or SP in sputum predicted clinical response to antibiotics; therefore, these tests are not necessary for outpatients with AECOPD. Examining Gram‐staining and purulence on sputum smear, however, was significant to predict PPB growth in sputum.
Necrotizing sarcoid granulomatosis: A distinctive form of pulmonary granulomatous disease
Authors: Karpathiou Georgia , Batistatou Anna , Boglou Panagiotis , Stefanou Dimitrios , Froudarakis Marios E.
Published: July 2017

Objectives

To define the characteristics of necrotizing sarcoid granulomatosis (NGS) a very rare pulmonary disease hardly recognised by pulmonologists and pathologists.

Data source

PubMed was searched for the term necrotising or necrotizing sarcoid granulomatosis.

Study selection

All cases reported in the English literature were included.

Results

NGS is presented at all ages (range 8‐68 years) with a median age of 42 years old. It shows female (62%) and Caucasian (80%) predominance. The most frequent symptoms are cough, fever, dyspnoea and chest pain. Extra‐pulmonary involvement is found in one third of the cases, with ocular being the most common (12.5%). At imaging, multiple nodules (64.75%) or a solitary mass (20.49%) are found accompanied by mediastinal lymphadenopathy at one third of the cases. It can be clinically mistaken for malignancy as it is tumour‐like, increases rapidly in size and it is hyperfixating in PET‐SCAN. Histologically, NGS is defined by large areas of necrosis, well‐formed granulomas and vascularitis.

Conclusion

NGS is a disease often confounded clinically with malignancy or with sarcoidosis even histologically when all criteria are not strictly applied. This review provides NGS' characteristics and discusses its differential diagnosis form sarcoidosis, Wegener granulomatosis and tuberculosis.
Diagnosis and treatment of community‐acquired pneumonia in adults: 2016 clinical practice guidelines by the Chinese Thoracic Society, Chinese Medical Association
Authors: Cao Bin , Huang Yi , She Dan‐Yang , Cheng Qi‐Jian , Fan Hong , Tian Xin‐Lun , Xu Jin‐Fu , Zhang Jing , Chen Yu , Shen Ning , Wang Hui , Jiang Mei , Zhang Xiang‐Yan , Shi Yi , He Bei , He Li‐Xian , Liu You‐Ning , Qu Jie‐Ming
Published: July 2017

Community‐acquired pneumonia (CAP) in adults is an infectious disease with high morbidity in China and the rest of the world. With the changing pattern in the etiological profile of CAP and advances in medical techniques in diagnosis and treatment over time, Chinese Thoracic Society of Chinese Medical Association updated its CAP guideline in 2016 to address the standard management of CAP in Chinese adults. Extensive and comprehensive literature search was made to collect the data and evidence for experts to review and evaluate the level of evidence. Corresponding recommendations are provided appropriately based on the level of evidence. This updated guideline covers comprehensive topics on CAP, including aetiology, antimicrobial resistance profile, diagnosis, empirical and targeted treatments, adjunctive and supportive therapies, as well as prophylaxis. The recommendations may help clinicians manage CAP patients more effectively and efficiently. CAP in pediatric patients and immunocompromised adults is beyond the scope of this guideline. This guideline is only applicable for the immunocompetent CAP patients aged 18 years and older. The recommendations on selection of antimicrobial agents and the dosing regimens are not mandatory. The clinicians are recommended to prescribe and adjust antimicrobial therapies primarily based on their local etiological profile and results of susceptibility testing, with reference to this guideline.
Can ADMA play a role in determining pulmonary hypertension related to chronic obstructive pulmonary disease?
Authors: Telo Selda , Kırkıl Gamze , Kuluöztürk Mutlu , Balin Mehmet , Deveci Figen
Published: July 2017

Background and aims

Asymmetric dimethylarginine (ADMA) decreases the levels of nitric oxide by inhibiting nitric oxide synthases. In this study, the possible role of ADMA in determining pulmonary hypertension (PH) in chronic obstructive pulmonary disease (COPD) patients was investigated.

Methods

Stable COPD patients who were admitted to pulmonology outpatient clinic were involved in the study. Forty healthy volunteers, with similar ages and sexes, were accepted as the control group. COPD patients were divided into two groups: 40 patients without PH (COPD group) and 40 COPD‐related PH patients (COPD‐PH group). Pulmonary function test, echocardiography and arterial blood analyses of all patients were performed.

Results

The mean age of patients was 69.21 ± 10.62, and 15 of these patients were females. There was no significant difference between the two COPD groups in terms of age and sex (P > .05). There was no difference in PaO2, SaO2, FEV1 and FEV1/FVC values between the two COPD groups (P > .05). Serum ADMA levels were similar in the control and the COPD group (0.42 ± 0.13 vs 0.43 ± 0.15), but it was significantly higher in the COPD‐PH group compared to the control and the COPD group (0.49 ± 0.14). A negative correlation was determined between serum ADMA levels and SaO2 levels (r = –.247, P = .028). A significant positive correlation observed between ADMA and systolic pulmonary artery pressure values (r = .627, P < .001)

Conclusions

In conclusion, high levels of serum ADMA levels may be able to determine the presence of PH.
Bolusing frequency and amount impacts glucose control during hybrid closed‐loop
Authors: Bally L. , Thabit H. , Ruan Y. , Mader J. K. , Kojzar H. , Dellweg S. , Benesch C. , Hartnell S. , Leelarathna L. , Wilinska M. E. , Evans M. L. , Arnolds S. , Pieber T. R. , Hovorka R.
Published: July 2017

Aim

To compare bolus insulin delivery patterns during closed‐loop home studies in adults with suboptimally [HbA1c 58–86 mmol/mol (7.5%–10%)] and well‐controlled [58 mmol/mol (< 7.5%)] Type 1 diabetes.

Methods

Retrospective analysis of daytime and night‐time insulin delivery during home use of closed‐loop over 4 weeks. Daytime and night‐time controller effort, defined as amount of insulin delivered by closed‐loop relative to usual basal insulin delivery, and daytime bolus effort, defined as total bolus insulin delivery relative to total daytime insulin delivery were compared between both cohorts. Correlation analysis was performed between individual bolus behaviour (bolus effort and frequency) and daytime controller efforts, and proportion of time spent within and below sensor glucose target range.

Results

Individuals with suboptimally controlled Type 1 diabetes had significantly lower bolus effort (P = 0.038) and daily bolus frequency (P < 0.001) compared with those with well‐controlled diabetes. Controller effort during both daytime (P = 0.007) and night‐time (P = 0.005) were significantly higher for those with suboptimally controlled Type 1 diabetes. Time when glucose was within the target range (3.9–10.0 mmol/L) during daytime correlated positively with bolus effort (r = 0.37, P = 0.016) and bolus frequency (r = 0.33, P = 0.037). Time when glucose was below the target range during daytime was comparable in both groups (P = 0.36), and did not correlate significantly with bolus effort (r = 0.28, P = 0.066) or bolus frequency (r = –0.21, P = 0.19).

Conclusion

More frequent bolusing and higher proportion of insulin delivered as bolus during hybrid closed‐loop use correlated positively with time glucose was in target range. This emphasises the need for user input and educational support to benefit from this novel therapeutic modality.
No calcitonin change in a person taking dulaglutide diagnosed with pre‐existing medullary thyroid cancer
Authors: Sherman S. I. , Kloos R. T. , Tuttle R. M. , Pontecorvi A. , Völzke H. , Harper K. , Vance C. , Alston J. T. , Usborne A. L. , Sloop K. W. , Lakshmanan M.
Published: July 2017

Background

Glucagon‐like peptide‐1 receptor agonists, such as dulaglutide, exenatide and liraglutide, are approved to treat Type 2 diabetes mellitus. Although these drugs provide substantial glycaemic control, studies in rodents have prompted concerns about the development of medullary thyroid carcinoma. These data are reflected in the US package insert, with boxed warnings and product labelling noting the occurrence of these tumours after clinically relevant exposures in rodents, and contraindicating glucagon‐like peptide‐1 receptor agonist use in people with a personal or family history of medullary thyroid carcinoma, or in people with multiple endocrine neoplasia type 2. However, there are substantial differences between rodent and human responses to glucagon‐like peptide‐1 receptor agonists. This report presents the case of a woman with pre‐existing medullary thyroid carcinoma who exhibited no significant changes in serum calcitonin levels despite treatment with dulaglutide 2.0 mg for 6 months in the Assessment of Weekly AdministRation of LY2189265 [dulaglutide] in Diabetes‐5 clinical study (NCT00734474).

Case report

Elevated serum calcitonin was noted in a 56‐year‐old woman with Type 2 diabetes mellitus at the 6‐month discontinuation visit in a study of long‐term dulaglutide therapy. Retroactive assessment of serum collected before study treatment yielded an elevated calcitonin level. At 3 months post‐study, calcitonin level remained elevated; ultrasonography revealed multiple bilateral thyroid nodules. Eventually, medullary thyroid carcinoma was diagnosed; the woman was heterozygous positive for a germline RET proto‐oncogene mutation.

Conclusion

The tumour was not considered stimulated by dulaglutide therapy because calcitonin remained stable throughout.
A first‐in‐human pharmacodynamic and pharmacokinetic study of a fully human anti‐glucagon receptor monoclonal antibody in normal healthy volunteers
Authors: Kostic Ana , King Thomas Alexander , Yang Feng , Chan Kuo‐Chen , Yancopoulos George D. , Gromada Jesper , Harp Joyce B.
Published: July 2017

Aims

Glucagon receptor (GCGR) blockers are being investigated as potential therapeutics for type 1 and type 2 diabetes. Here we report the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of REGN1193, a fully human glucagon receptor blocking monoclonal antibody from a first‐in‐human healthy volunteer randomized double‐blinded trial.

Methods

Healthy men and women received single ascending doses of REGN1193 ranging from 0.05 to 0.6 mg/kg (n = 42) or placebo (n = 14) intravenously. Safety, tolerability and PK were assessed over 106 days. The glucose‐lowering effect of REGN1193 was assessed after induction of hyperglycaemia by serial glucagon challenges.

Results

REGN1193 was generally well tolerated. There were small (<3× the upper limit of normal) and transient dose‐dependent increases in hepatic aminotransferases. No increase in LDL‐C was observed. Hypoglycaemia, assessed as laboratory blood glucose ≤70 mg/dL, occurred in 6/14 (43%) subjects on placebo and 27/42 (57%) on REGN1193 across all dose groups. All episodes of hypoglycaemia were asymptomatic, >50 mg/dL, and did not require treatment or medical assistance. Concentration‐time profiles suggest a 2‐compartment disposition and marked nonlinearity, consistent with target‐mediated clearance. REGN1193 inhibited the glucagon‐stimulated glucose increase in a dose‐dependent manner. The 0.6 mg/kg dose inhibited the glucagon‐induced glucose area under the curve for 0 to 90 minutes (AUC0‐90 minutes) by 80% to 90% on days 3 and 15, while blunting the increase in C‐peptide. REGN1193 dose‐dependently increased total GLP‐1, GLP‐2 and glucagon, with plasma levels returning to baseline by day 29 in all dose groups.

Conclusion

REGN1193, a GCGR‐blocking monoclonal antibody, produced a safety, tolerability and PK/PD profile suitable for further clinical development. The occurrence of transient elevations in serum hepatic aminotransferases observed here and reported with several small molecule glucagon receptor antagonists suggests an on‐target effect of glucagon receptor blockade. The underlying mechanism is unknown.
Love thy neighbour: Social identity and public support for humanitarian aid
Authors: Alvarez Linda , Boussalis Constantine , Merolla Jennifer L. , Peiffer Caryn A.
Published: July 2017

Humanitarian aid can be contentious. Should finite national resources be sacrificed to serve the needy abroad? Social identity theorists argue that identification with a superordinate group, in this case the larger world community, should increase individual support for policies such as international humanitarian assistance. However, individuals can simultaneously associate with multiple identities. How does the combination of world and national identities affect support for humanitarian assistance? Using cross‐national survey data, we find evidence that support for international humanitarian aid is highest among those with a strong world identity and weak national identity relative to other identity combinations, though even those with a strong world identity and strong national identity can be supportive of aid.
Molecular characterization of a phytoplasma associated with Euonymus bungeanus witches’ broom in China
Authors: Ren Z. G. , Zhao X. Y. , Dong Y. R. , Wang J. Z. , Yang R. , Wang S. J. , Tian G. Z. , Wei Y. M.
Published: July 2017

Euonymus bungeanus plants exhibiting symptoms of abnormal branches, small leaves and phyllody, which is indicative of E. bungeanus witches’ broom (EbWB) disease, have recently been found in Beijing, China. A phytoplasma from symptomatic E. bungeanus plants was identified by 16S rRNA polymerase chain reaction (PCR) using the phytoplasma‐specific universal primer pair R16mF2/R16mR1. Inoculation of healthy E. bungeanus plants by grafting with diseased scions was also performed. The rp and secY genes of the EbWB phytoplasma were cloned and sequenced as was the 16S rRNA gene. Sequence and phylogenetic analyses of 16S rRNA, rp and secY genes indicated that the phytoplasma associated with E. bungeanus belongs to the 16SrV‐B, rpV‐C and secY‐C subgroup, the same subgroup as the jujube witches’ broom (JWB) phytoplasma that is widely distributed among jujube trees in China. Comparative analyses based on virtual restriction fragment length polymorphism (RFLP) showed that the EbWB phytoplasma is more closely related to another 16SrV‐B subgroup strain: RPWB (Robinia pseudoacacia witches’ broom). To the best of our knowledge, this is the first report of a witches’ broom phytoplasma in E. bungeanus in China, and the findings add a new cultivated plant species to the already broad natural host range of 16SrV‐B subgroup phytoplasmas.
Optimal metabolic regulation along resource stoichiometry gradients
Authors: Manzoni Stefano , Čapek Petr , Mooshammer Maria , Lindahl Björn D. , Richter Andreas , Šantrůčková Hana
Published: July 2017

Most heterotrophic organisms feed on substrates that are poor in nutrients compared to their demand, leading to elemental imbalances that may constrain their growth and function. Flexible carbon (C)‐use efficiency (CUE, C used for growth over C taken up) can represent a strategy to reduce elemental imbalances. Here, we argue that metabolic regulation has evolved to maximise the organism growth rate along gradients of nutrient availability and translated this assumption into an optimality model that links CUE to substrate and organism stoichiometry. The optimal CUE is predicted to decrease with increasing substrate C‐to‐nutrient ratio, and increase with nutrient amendment. These predictions are generally confirmed by empirical evidence from a new database of c. 2200 CUE estimates, lending support to the hypothesis that CUE is optimised across levels of organisation (microorganisms and animals), in aquatic and terrestrial systems, and when considering nitrogen or phosphorus as limiting nutrients.
G3BP1 interacts directly with the FMDV IRES and negatively regulates translation
Authors: Galan Alfonso , Lozano Gloria , Piñeiro David , Martinez‐Salas Encarnacion
Published: July 2017

RNA–protein interactions play a pivotal role in the function of picornavirus internal ribosome entry site (IRES) elements. Here we analysed the impact of Ras GTPase SH3 domain binding protein 1 (G3BP1) in the IRES activity of foot‐and‐mouth disease virus (FMDV). We found that G3BP1 interacts directly with three distinct sequences of the IRES element using RNA electrophoretic mobility‐shift assays. Analysis of the interaction with domain 5 indicated that the G3BP1 binding‐site is placed at the single‐stranded region although it allows large sequence heterogeneity and the hairpin located upstream of this region enhances retarded complex formation. In addition, G3BP1 interacts directly with the polypyrimidine tract‐binding protein and the translation initiation factor 4B (eIF4B) through the C‐terminal region. Moreover, G3BP1 is cleaved during FMDV infection yielding two fragments, Ct‐G3BP1 and Nt‐G3BP1. Both fragments inhibit cap‐ and IRES‐dependent translation, but the Ct‐G3BP1 fragment shows a stronger effect on IRES‐dependent translation. Assembly of complexes with G3BP1 results in a significantly reduced local flexibility of the IRES element, consistent with the negative effect of this protein. Our results highlight the IRES‐binding capacity of G3BP1 and illustrate its function as a translation inhibitor.
Regulation of the interaction between the neuronal BIN1 isoform 1 and Tau proteins – role of the SH3 domain
Authors: Malki Idir , Cantrelle François‐Xavier , Sottejeau Yoann , Lippens Guy , Lambert Jean‐Charles , Landrieu Isabelle
Published: July 2017

Bridging integrator 1 (bin1) gene is a genetic determinant of Alzheimer's disease (AD) and has been reported to modulate Alzheimer's pathogenesis through pathway(s) involving Tau. The functional impact of Tau/BIN1 interaction as well as the molecular details of this interaction are still not fully resolved. As a consequence, how BIN1 through its interaction with Tau affects AD risk is also still not determined. To progress in this understanding, interaction of Tau with two BIN1 isoforms was investigated using Nuclear Magnetic Resonance spectroscopy. 1H, 15N spectra showed that the C‐terminal SH3 domain of BIN1 isoform 1 (BIN1Iso1) is not mobile in solution but locked with the core of the protein. In contrast, the SH3 domain of BIN1 isoform 9 (BIN1Iso9) behaves as an independent mobile domain. This reveals an equilibrium between close and open conformations for the SH3 domain. Interestingly, a 334–376 peptide from the clathrin and AP‐2‐binding domain (CLAP) domain of BIN1Iso1, which contains a SH3‐binding site, is able to compete with BIN1‐SH3 intramolecular interaction. For both BIN1 isoforms, the SH3 domain can interact with Tau(210–240) sequence. Tau(210–240) peptide can indeed displace the intramolecular interaction of the BIN1‐SH3 of BIN1Iso1 and form a complex with the released domain. The measured Kd were in agreement with a stronger affinity of Tau peptide. Both CLAP and Tau peptides occupied the same surface on the BIN1‐SH3 domain, showing that their interaction is mutually exclusive. These results emphasize an additional level of complexity in the regulation of the interaction between BIN1 and Tau dependent of the BIN1 isoforms.
Variable silicon accumulation in plants affects terrestrial carbon cycling by controlling lignin synthesis
Authors: Klotzbücher Thimo , Klotzbücher Anika , Kaiser Klaus , Vetterlein Doris , Jahn Reinhold , Mikutta Robert
Published: July 2017

Current climate and land‐use changes affect regional and global cycles of silicon (Si), with yet uncertain consequences for ecosystems. The key role of Si in marine ecology by controlling algae growth is well recognized but research on terrestrial ecosystems neglected Si since not considered an essential plant nutrient. However, grasses and various other plants accumulate large amounts of Si, and recently it has been hypothesized that incorporation of Si as a structural plant component may substitute for the energetically more expensive biosynthesis of lignin. Herein, we provide evidence supporting this hypothesis. We demonstrate that in straw of rice (Oryza sativa) deriving from a large geographic gradient across South‐East Asia, the Si concentrations (ranging from 1.6% to 10.7%) are negatively related to the concentrations of carbon (31.3% to 42.5%) and lignin‐derived phenols (32 to 102 mg/g carbon). Less lignin may explain results of previous studies that Si‐rich straw decomposes faster. Hence, Si seems a significant but hardly recognized factor in organic carbon cycling through grasslands and other ecosystems dominated by Si‐accumulating plants.
Prostate carcinoma with amphicrine features: further refining the spectrum of neuroendocrine differentiation in tumours of primary prostatic origin?
Authors: Prendeville Susan , Al‐Bozom Issam , Compérat Eva , Sweet Joan , Evans Andrew J , Ben‐Gashir Mohamed , Mete Ozgur , van der Kwast Theodorus H , Downes Michelle R
Published: July 2017

Aims

The current World Health Organization classification categorises high‐grade neuroendocrine (NE) carcinomas of the prostate into small‐cell and large‐cell types. A distinct form of carcinoma showing synchronous dual exocrine and NE differentiation, termed amphicrine carcinoma, has been described at various other sites, primarily within the gastrointestinal tract. The aim of this study was to investigate the clinicopathological features of a series of metastatic prostate carcinoma (PCa) cases with amphicrine features.

Methods and results

Five cases of high‐grade PCa showing an amphicrine immunohistochemical phenotype were prospectively collected. The serum prostate‐specific antigen (PSA) level at diagnosis ranged from 38 ng/ml to 992 ng/ml (median 200 ng/ml). All five patients had metastatic disease, four at initial presentation. Microscopically, the tumours showed a solid/nested growth pattern composed of cells with amphophilic cytoplasm, vesicular nuclei, and macronucleoli. Morphological features of small‐cell or large‐cell NE carcinoma were absent. As compared with conventional high‐grade PCa, the tumour cells showed a higher level of nuclear pleomorphism, brisk mitotic activity, and a high Ki67 proliferation index (median 50%). All cases showed immunohistochemical positivity for PSA, androgen receptor, and prostate‐specific acid phosphatase, combined with diffuse or confluent/non‐focal positivity for chromogranin‐A and synaptophysin. Two hormone‐naive cases showed a clinical response to androgen deprivation therapy.

Conclusion

This series highlights a previously undefined, clinically aggressive variant of PCa showing dual exocrine and NE differentiation, for which we are proposing the term PCa with amphicrine features. Increased recognition of these tumours may lead to a better understanding of their biology, and ultimately improve their clinical management.
Killer‐cell immunoglobulin‐like receptors on the cusp of modern immunogenetics
Authors: Colucci Francesco , Traherne James
Published: July 2017

Killer‐cell immunoglobulin‐like receptors (KIR) and their human leukocyte antigen (HLA) ligands play a central role in immunity and human health. These molecules are encoded by gene families with copy number variation, extreme levels of sequence diversity and complex expression patterns. The rapid evolution of KIR and HLA genes and their associations with infectious diseases, pregnancy disorders, immunopathologies and outcome of cell transplantation have generated considerable interest from immunologists, geneticists and clinicians. Until recently, however, analyses have been stuck at low‐level resolution, focusing primarily on presence or absence of KIR genes. This is changing with the advent of modern high throughput sequencing, cell phenotyping and bioinformatics. These developments allow high‐resolution analysis and much deeper understanding of KIR evolution and KIR function. The impending deluge of high dimensional data brings inevitably new challenges in analysis, interpretation and communication of results, but the benefits are already tangible. The diversity of KIR across worldwide human populations is being catalogued at the allele level. Structures of KIR molecules and their interactions with HLA–peptide complexes are being determined. How KIR modulate natural killer cell education is being defined. Ligands for activating KIR, elusive for many years, are being discovered. KIR gene complexes and their related receptor gene families are being characterized in animal models and livestock breeds. These advances are helping to generate a more complete picture of the impact of KIR variation in health and disease and offer new opportunities for immunotherapy, as highlighted in a recent meeting (The Tenth KIR Workshop, April 2017 Cambridge, UK).
RNomic identification and evaluation of npcTB_6715, a non‐protein‐coding RNA gene as a potential biomarker for the detection of Mycobacterium tuberculosis
Authors: Kanniappan Priyatharisni , Ahmed Siti Aminah , Rajasekaram Ganeswrie , Marimuthu Citartan , Ch'ng Ewe Seng , Lee Li Pin , Raabe Carsten A. , Rozhdestvensky Timofey S. , Tang Thean Hock
Published: July 2017

Technological advances in RNA biology greatly improved transcriptome profiling during the last two decades. Besides the discovery of many small RNAs (sRNA) that are involved in the physiological and pathophysiological regulation of various cellular circuits, it becomes evident that the corresponding RNA genes might also serve as potential biomarkers to monitor the progression of disease and treatment. sRNA gene candidate npcTB_6715 was previously identified via experimental RNomic (unpublished data), and we report its application as potential biomarker for the detection of Mycobacterium tuberculosis (MTB) in patient samples. For proof of principle, we developed a multiplex PCR assay and report its validation with 500 clinical cultures, positive for Mycobacteria. The analysis revealed 98.9% sensitivity, 96.1% specificity, positive and negative predictive values of 98.6% and 96.8%, respectively. These results underscore the diagnostic value of the sRNA gene as diagnostic marker for the specific detection of MTB in clinical samples. Its successful application and the general ease of PCR‐based detection compared to standard bacterial culture techniques might be the first step towards ‘point‐of‐care’ diagnostics of Mycobacteria. To the best of our knowledge, this is the first time for the design of diagnostic applications based on sRNA genes, in Mycobacteria.
Frailty as a Risk Factor for Falls Among Community Dwelling People: Evidence From a Meta‐Analysis
Authors: Cheng Mei‐Hsun , Chang Shu‐Fang
Published: July 2017

Purpose

This study was conducted to investigate the relationships between different frailty stages and the fall incidence rates of community‐dwelling older adults. The differences between various frailty indicators regarding assessment accuracy of the fall incidence rates of community‐dwelling elders were also analyzed. Finally, the relationship between frailty and recurrent falls was explored.

Methods

This study comprised a systematic literature review and meta‐analysis. Two researchers independently examined and extracted the related literature. The key search terms included frailty, frail, fall, older people, older, geriatric, and senior. The literature sampling period was from January 2001 to December 2016. The quality of each paper was assessed according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA). The databases of the Cochrane Library, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PubMed, and MEDLINE were used to conduct a systematic literature search by using the random effect mode to analyze the compiled papers.

Findings

A total of 102,130 community‐dwelling older adults ≥65 years of age and 33,503 older adults who had experienced a fall were compiled to investigate the relationship between frailty and falls. The meta‐analysis results revealed that compared with robust older adults, frail older adults demonstrated the greatest risk for falls, followed by prefrail older adults. Furthermore, the use of different frailty indicators to predict the fall incidence rates of older adults yielded nonsignificantly different outcomes. In short, studies of either cardiovascular health or osteoporotic fracture indicators are effective for predicting the risk for falls in older people. Finally, this study confirmed that compared with robust older adults, frail older adults were more likely to experience recurrent falls.

Conclusions

Frailty is a crucial healthcare topic of people with geriatric syndromes. Frail older adults are likely to experience recurrent falls. In addition, the evidence‐based study indicated that once older people enter the prefrail stage, they are likely to experience falls. Therefore, older adults should be evaluated for the possibility of geriatric syndromes such as frailty, which may be addressed to reduce the risk for bone fractures and death.

Clinical Relevance

Professional nurses should use frailty assessment indicators as early as possible to evaluate the possibility of frailty in community‐dwelling older people. Meanwhile, effective frailty prevention strategies should be applied to prevent frailty, thereby reducing the incidence of falls and enhancing older persons’ quality of life.
Association between Gallbladder Ultrasound Findings and Bacterial Culture of Bile in 70 Cats and 202 Dogs
Authors: Policelli Smith R. , Gookin J.L. , Smolski W. , Di Cicco M.F. , Correa M. , Seiler G.S.
Published: July 2017

Background

Bacterial cholecystitis often is diagnosed by combination of gallbladder ultrasound (US) findings and positive results of bile culture. The value of gallbladderUSin determining the likelihood of bile bacterial infection in cats and dogs with suspected biliary disease is unknown.

Hypothesis/Objectives

To determine the value of gallbladderUSin predicting bile bacterial culture results, identify most common bacterial isolates from bile, and describe complications after cholecystocentesis in cats and dogs with suspected hepatobiliary disease.

Animals

Cats (70) and dogs (202) that underwent an abdominalUSand submission of bile for culture were included in the study.

Methods

A cross‐sectional study design was used to determine the association of gallbladderUSabnormalities and the results of bile cultures, and complications of cholecystocentesis.

Results

Abnormal gallbladderUShad high sensitivity (96%) but low specificity (49%) in cats with positive and negative results of bile bacterial culture, respectively. Cats with normal gallbladderUSfindings were unlikely to have positive bile bacterial culture (negative predictive value of 96%). GallbladderUShad lower sensitivity (81%), specificity (31%), positive predictive value (20%), and negative predictive value (88%) in dogs. The most common bacterial isolates were of enteric origin, the prevalence being higher in cats. Incidence of complications after cholecystocentesis was 3.4%.

Conclusions and clinical importance

GallbladderUShas a high negative predictive value for bile culture results in cats. This modality is less predictive of infection in dogs. PercutaneousUS‐guided cholecystocentesis has a low complication rate.
Randomized, Controlled, Crossover trial of Prevention of Clindamycin‐Induced Gastrointestinal Signs Using a Synbiotic in Healthy Research Cats
Authors: Stokes J.E. , Price J.M. , Whittemore J.C.
Published: July 2017

Background

Synbiotics often are prescribed to limit antibiotic‐associated gastrointestinal signs (AAGS) in cats, but data to support this recommendation are lacking.

Objective

To determine whether synbiotic co‐administration mitigates AAGS in healthy research cats treated with clindamycin.

Animals

16 healthy research cats.

Methods

A randomized, double‐blinded, placebo‐controlled, 2‐way, 2‐period, crossover study with a 6‐week washout was performed. Each study period consisted of a 1‐week baseline and a 3‐week treatment period. Cats received 75 mg clindamycin with food once daily for 3 weeks, followed 1 hour later by either 2 capsules of a synbiotic or placebo. Food consumption, vomiting, fecal score, and completion of treatment were compared using repeated measures split plot or crossover designs with covariates, with P < 0.05 considered significant.

Results

Cats that received the synbiotic were more likely to complete treatment in period 1 (100% vs. 50%, P = 0.04). Cats vomited less when receiving the synbiotic but this was not significant, but there were significant period effects (F‐value = 11.4, P < 0.01). Cats had higher food intake while receiving the synbiotic (F‐value = 31.1, P < 0.01) despite period effects (F‐value = 8.6, P < 0.01). There was no significant effect of treatment on fecal scores, which significantly increased over time (F‐value = 17.9, P < 0.01).

Conclusions and Clinical Importance

Administration of a synbiotic 1 hour after clindamycin administration decreased hyporexia and vomiting in healthy cats. Additionally, significant period effects suggest that clinical benefits of synbiotic administration persist for at least 6 weeks after discontinuation, decreasing the severity of AAGS in cats that subsequently received clindamycin with placebo. Unlike in people, synbiotic administration did not decrease antibiotic‐associated diarrhea.
Sofosbuvir/velpatasvir in patients with hepatitis C virus genotypes 1‐6 and compensated cirrhosis or advanced fibrosis
Authors: Asselah Tarik , Bourgeois Stefan , Pianko Stephen , Zeuzem Stefan , Sulkowski Mark , Foster Graham R. , Han Lingling , McNally John , Osinusi Anu , Brainard Diana M. , Subramanian G. Mani , Gane Edward J. , Feld Jordan J. , Mangia Alessandra
Published: July 2017

Background & Aims

Patients with chronic hepatitis C virus infection and advanced fibrosis (Metavir F3) or cirrhosis (Metavir F4) have been identified as a priority group for immediate treatment. We evaluated the safety and efficacy of sofosbuvir‐velpatasvir in patients with hepatitis C virus genotype 1‐6 infection and compensated cirrhosis or advanced fibrosis.

Methods

This retrospective analysis included 501 patients with compensated cirrhosis or advanced fibrosis (F3/F4), as defined by >0.59 on Fibrotest, >9.5 kPa on Fibroscan, or F3/F4 (Metavir) or F4 (Ishak) on liver biopsy. Patients received sofosbuvir‐velpatasvir for 12 weeks. Sustained virological response 12 weeks after treatment was determined.

Results

Forty‐four per cent of patients had cirrhosis. Sustained virological response 12 weeks after treatment was achieved by 98% of patients (490/501; 95% confidence interval, 96‐99). Sustained virological response 12 weeks after treatment rates were 100% for hepatitis C virus genotypes 2 (85/85), 4 (60/60), 5 (13/13), and 6 (20/20). Sustained virological response 12 weeks after treatment rates were 98% (167/170) in hepatitis C virus genotype 1 patients and 95% (145/153) in hepatitis C virus genotype 3 patients. Among patients with cirrhosis 96% (212/220) achieved sustained virological response 12 weeks after treatment, vs 99% (278/281) for those with advanced fibrosis. Sustained virological response 12 weeks after treatment was 98% (306/311) for treatment‐naïve patients and 97% (184/190) for treatment‐experienced patients. No patients discontinued treatment due to adverse events. Eight patients reported nine serious adverse events; none was considered related to study procedures or drugs.

Conclusions

Sofosbuvir plus velpatasvir is highly effective and safe for treating patients with hepatitis C virus genotypes 1, 2, 3, 4, 5 or 6 and advanced fibrosis or compensated cirrhosis.
Signalling requirements for Erwinia amylovora‐induced disease resistance, callose deposition and cell growth in the non‐host Arabidopsis thaliana
Authors: Hamdoun Safae , Gao Min , Gill Manroop , Kwon Ashley , Norelli John L. , Lu Hua
Published: July 2017

Erwinia amylovora is the causal agent of the fire blight disease in some plants of the Rosaceae family. The non‐host plant Arabidopsis serves as a powerful system for the dissection of mechanisms of resistance to E. amylovora. Although not yet known to mount gene‐for‐gene resistance to E. amylovora, we found that Arabidopsis activated strong defence signalling mediated by salicylic acid (SA), with kinetics and amplitude similar to that induced by the recognition of the bacterial effector avrRpm1 by the resistance protein RPM1. Genetic analysis further revealed that SA signalling, but not signalling mediated by ethylene (ET) and jasmonic acid (JA), is required for E. amylovora resistance. Erwinia amylovora induces massive callose deposition on infected leaves, which is independent of SA, ET and JA signalling and is necessary for E. amylovora resistance in Arabidopsis. We also observed tumour‐like growths on E. amylovora‐infected Arabidopsis leaves, which contain enlarged mesophyll cells with increased DNA content and are probably a result of endoreplication. The formation of such growths is largely independent of SA signalling and some E. amylovora effectors. Together, our data reveal signalling requirements for E. amylovora‐induced disease resistance, callose deposition and cell fate change in the non‐host plant Arabidopsis. Knowledge from this study could facilitate a better understanding of the mechanisms of host defence against E. amylovora and eventually improve host resistance to the pathogen.