bluuebunny/crossref_metadata_2025 huggingface dataset:
Heart rate variability as a predictor of hypotension following spinal for elective caesarean section: a prospective observational study
Authors: Bishop D. G. , Cairns C. , Grobbelaar M. , Rodseth R. N.
Published: January 2017

Post‐spinal hypotension remains a common and clinically‐important problem during caesarean section, and accurate pre‐operative prediction of this complication might enhance clinical management. We conducted a prospective, single‐centre, observational study of heart rate variability in 102 patients undergoing elective caesarean section in a South African regional hospital. We performed Holter recording for ≥ 5 min in the hour preceding spinal anaesthesia. The low‐frequency/high‐frequency ratio component of heart rate variability was compared, using a logistic regression model, with baseline heart rate and body mass index (BMI) as a predictor of hypotension (defined as systolic arterial pressure < 90 mmHg) occurring from the time of spinal insertion until 15 min after delivery of the baby. We also assessed clinically relevant cut‐point estimations for low‐frequency/high‐frequency ratio. Low‐frequency/high‐frequency ratio predicted hypotension (p = 0.046; OR 1.478, 95%CI 1.008‐1.014), with an optimal cut‐point estimation of 2.0; this threshold predicted hypotension better than previously determined thresholds (p = 0.003; c‐statistic 0.645). Baseline heart rate (p = 0.20; OR 1.022, 95%CI 0.988‐1.057) and BMI (p = 0.60; OR 1.017, 95%CI 0.954‐1.085) did not predict hypotension. Heart rate variability analysis is a potentially useful clinical tool for the prediction of hypotension. Future studies should consider a low‐frequency/high‐frequency ratio threshold of 2.0 for prospective validation.
New parameters in assessment of human donor corneal stroma
Authors: Borderie Marie , Grieve Kate , Irsch Kristina , Ghoubay Djida , Georgeon Cristina , De Sousa Celine , Laroche Laurent , Borderie Vincent M.
Published: January 2017

Purpose

To provide quantitative parameters for assessment of human donor corneal stroma by imaging stromal features of diseased and normal human corneas with full‐field optical coherence microscopy (FFOCM), using confocal microscopy (CM) and histology as reference techniques.

Methods

Bowman's layer (BL) thickness and keratocyte density were assessed ex vivo in 23 human donor corneas and 27 human pathological corneas (keratoconus and other corneal disorders) with FFOCM, CM and histology. Stromal backscattering was assessed with FFOCM. Additionally, 10 normal human corneas were assessed in vivo with CM.

Results

In FFOCM, the logarithm of the normalized stromal reflectivity was a linear function of stromal depth (R2 = 0.95) in human donor corneas. Compared with keratoconus corneas, human donor corneas featured higher BL thickness (p = 0.0014) with lower coefficient of variation (BL‐COV; p = 0.0002), and linear logarithmic stromal reflectivity with depth (higher R2, p = 0.0001). Compared with other corneal disorders, human donor corneas featured lower BL‐COV (p = 0.012) and higher R2 (p = 0.0001). Using the 95% confidence limits of the human donor cornea group, BL thickness < 6.5 μm (sensitivity, 57%; specificity, 100%), BL‐COV > 18.6% (79%; 100%) and R2 < 0.94 (93%; 71%) were revealed as indictors of abnormal cornea. In CM, keratocyte density decreased with stromal depth (r = −0.56). The mean overall keratocyte density (cells/mm2) was 205 in human donor corneas, 244 in keratoconus, 176 in other corneal disorders and 386 in normal corneas.

Conclusion

Full‐field optical coherence microscopy (FFOCM) provides precise and reliable parameters for non‐invasive assessment of human donor corneal stroma during storage, enabling detection of stromal disorders that could impair the results of keratoplasty.
Differential effects of film on preschool children's behaviour dependent on editing pace
Authors: Kostyrka‐Allchorne Katarzyna , Cooper Nicholas R. , Gossmann Anna Maria , Barber Katy J. , Simpson Andrew
Published: January 2017

Aim

Evidence on how the pace of television and film editing affects children's behaviour and attention is inconclusive. We examined whether a fast‐paced film affected how preschool‐aged children interacted with toys.

Methods

The study comprised 70 children (36 girls) aged two to four‐and‐a‐half years who attended preschools in Essex, United Kingdom. The children were paired up and tested with either a fast‐ or a slow‐paced film of a narrator reading a children's story. The fast‐paced version had 102 camera cuts and 16 still images, and the slow‐paced version had 22 camera cuts and four still images. Each dyad took part in two video‐recorded free‐play sessions, before and after they watched one of the specially edited four‐minute films. The number of toys the children played with before and after the film sessions was recorded.

Results

Before they watched the films, the children's behaviour did not differ between the groups. However, after watching the film, the children in the fast‐paced group shifted their attention between toys more frequently than the children who watched the slow‐paced film.

Conclusion

Even a brief exposure to differently paced films had an immediate effect on how the children interacted with their toys.
UNDERSTANDING COOPERATIVE FINANCE AS A NEW COMMON
Authors: PÉRILLEUX Anaïs , NYSSENS Marthe
Published: January 2017

The emerging field of common good socio‐economics is promising not only for the preservation of common natural resources but also for common goods created by people through collective action, the importance of which has been emphasized by the recent financial and economic crisis. Based on the case of cooperative finance, this paper's outcomes are twofold. First, it shows that while the boundaries between the nature and property regime of goods may be relatively clear for natural common goods, they appear much more interlinked for human‐made goods, where commons are embedded in intergenerational reciprocity. Second, it demonstrates that financial cooperatives can be understood as human‐made commons and proposes a new way of thinking about public policies to design adequate legislation to protect these commons from isomorphism, privatization and destruction.
Pharmacokinetics, safety, tolerability and immunogenicity of FKB327, a new biosimilar medicine of adalimumab/Humira, in healthy subjects
Authors: Puri Adeep , Niewiarowski Andrew , Arai Yasumasa , Nomura Hideaki , Baird Mark , Dalrymple Isobel , Warrington Steve , Boyce Malcolm
Published: January 2017

Aims

To compare the pharmacokinetics, safety, tolerability and immunogenicity of FKB327, a biosimilar of adalimumab, with European Union (EU)‐approved Humira and US‐licensed Humira after single subcutaneous doses in healthy subjects.

Methods

In a randomized, double‐blind, parallel‐group study, 180 healthy subjects received by subcutaneous injection 40 mg of EU‐Humira, or US‐Humira, or FKB327, in a 1:1:1 ratio, stratified by bodyweight. Pharmacokinetics, local tolerability, immunogenicity, adverse events, vital signs, electrocardiography and laboratory safety tests were assessed prior to and up to 1536 h after treatment.

Results

The pharmacokinetics of FKB327 were similar to those of both EU‐ and US‐Humira. The 90% confidence interval for the ratios of AUC0–t, AUC0–inf, and Cmax geometric means were in the acceptance range for bioequivalence of 0.80–1.25 for all three pairwise comparisons by analysis of covariance with baseline characteristics age, body weight and (for Cmax only) sex as covariates. Tolerability of all three treatments was equally acceptable, and there were no differences in safety profile or immunogenicity among the three treatments. Overall, antidrug antibodies were detected in approximately 70% of subjects who received each treatment; higher titres were associated with faster elimination of adalimumab.

Conclusions

The study demonstrated pharmacokinetic similarity of FKB327 with EU‐ and US‐Humira. FKB327 was well tolerated by healthy subjects, with adverse effects similar to Humira. If clinical similarity to Humira, including efficacy, can be shown in patients, FKB327 will meet the criteria for biosimilarity to Humira.
Dual targeting of vascular endothelial growth factor and bone morphogenetic protein‐9/10 impairs tumor growth through inhibition of angiogenesis
Authors: Akatsu Yuichi , Yoshimatsu Yasuhiro , Tomizawa Taishi , Takahashi Kazuki , Katsura Akihiro , Miyazono Kohei , Watabe Tetsuro
Published: January 2017

Clinical development of anti‐angiogenic agents has been a major landmark in cancer therapy for several types of cancers. Signals mediated by both vascular endothelial growth factor (VEGF) and bone morphogenetic protein (BMP)‐9 and 10 have been implicated in tumor angiogenesis. However, previous studies have shown that targeting the individual signals was not sufficiently effective in retarding tumor growth in certain preclinical and clinical conditions. In the present study, we developed a novel decoy chimeric receptor that traps both VEGF and BMP‐9/10. Single targeting of either VEGF or BMP‐9/10 signals significantly reduced the formation of tumor vessels in a mouse xenograft model of human pancreatic cancer; however, it did not show significant therapeutic effects on tumor growth. In contrast, dual targeting of the angiogenic signals resulted in more significant inhibition of tumor angiogenesis, leading to delay of tumor growth. Our findings suggest that simultaneous blockade of VEGF and BMP‐9/10 signals is a promising therapeutic strategy for the cancers that are resistant to anti‐VEGF and BMP‐9/10 therapies.
Radiosensitivity of quiescent and proliferating cells grown as multicellular tumor spheroids
Authors: Onozato Yusuke , Kaida Atsushi , Harada Hiroyuki , Miura Masahiko
Published: January 2017

The multicellular spheroid model partly mimics tumor microenvironments in vivo and has been reported in plenty of studies regarding radiosensitivity. However, clear isolation of quiescent and proliferating cells in live conditions has been quite difficult owing to technical limitations; therefore, comprehensive characterization could not be done thus far. In this study, we succeeded in separately isolating different cell types using a fluorescent ubiquitination‐based cell cycle indicator (Fucci) and determining their radiosensitivities. Unexpectedly, proliferating cells were more radioresistant than quiescent cells due to the contact effect when spheroids were disaggregated immediately after irradiation. However, the radiosensitivity of quiescent cells was not influenced by mild hypoxia (hypoxia‐inducible factor‐1α‐positive but pimonidazole‐negative), but their radioresistance became similar to that of proliferating cells due to potentially lethal damage repair when disaggregated 24 h after irradiation. The Fucci system further allowed long‐term observation of cell kinetics inside of the spheroid following irradiation using real‐time confocal fluorescence scanning. Repeated cycles of recruitment from the quiescent to the proliferating phase resulted in cell loss from the outside of the spheroid toward the inside, causing gradual shrinkage. Interestingly, the central region of the spheroid entered a dormant stage approximately 40 days after irradiation and survived for more than 2 months. Using the Fucci system, we were able to comprehensively characterize the radiosensitivity of spheroids for the first time, which highlights the importance of cell cycle kinetics after irradiation in determining the radiosensitivity under tumor microenvironments.
Alcohol use, alcohol‐related aggression and intimate partner abuse: A cross‐sectional survey of convicted versus general population men in Scotland
Authors: Gilchrist Elizabeth Allison , Ireland Lana , Forsyth Alasdair , Godwin Jon , Laxton Tim
Published: January 2017

Introduction and Aims

Scotland has a particular problem with alcohol, and the links between intimate partner abuse (IPA) and alcohol appear stronger here than elsewhere across Europe. This study explored differences in alcohol use, related aggression and relationship conflict across a number of groups: men convicted for intimate partner abuse, men convicted of general offences and men recruited from community sports teams.

Design and Methods

Participants (n = 64) completed three questionnaires exploring their experiences of alcohol use (Alcohol Use Disorders Identification Test, AUDIT); alcohol and aggression (Alcohol Related Aggression Questionnaire, ARAQ‐28), and relationship conflict (Revised Conflict Tactics Scale, CTS‐2).

Results

There were significant differences across the groups in terms of AUDIT and ARAQ‐28 scores, IPA and general offenders scored higher than the community sample. CTS‐2 scores showed significant differences: both offender groups reported more use of negotiation and psychological abuse, than the community men, and IPA offenders reported causing more physical harm than either general offenders or the community sample. ARAQ‐28 scores correlated with psychological abuse for general offenders. Alcohol use was very high across all groups, but the community group did not endorse an aggression‐precipitating view of alcohol and did not report high IPA.

Discussion and Conclusions

Discussed is the need for cross‐cultural research to explore putative mediators and moderators in the relationship between alcohol, aggressiveness and IPA. [Gilchrist EA, Ireland L, Forsyth A, Godwin J, Laxton T. Alcohol use, alcohol‐related aggression and intimate partner abuse: A cross‐sectional survey of convicted versus general population men in Scotland. Drug Alcohol Rev 2017;36:20–23]
Factors affecting the United Nations' response to natural disasters: what determines the allocation of the Central Emergency Response Fund?
Authors: Robinson Tyler D. , Oliveira Thiago M. , Kayden Stephanie
Published: January 2017

Natural disasters can overwhelm the domestic response of a country, leaving it dependent on external humanitarian relief. The Central Emergency Response Fund (CERF) of the United Nations centralises humanitarian funding and thus allows for a rapid response. This study combined data to analyse the factors that affected the allocation of CERF funding to countries that suffered a natural disaster between 2007 and 2013. It generated descriptive statistics and information on relative risks, and performed regressions of CERF funding across countries. There were 4,346 disasters in total in 188 countries between 2007 and 2013. CERF provided USD 2.98 billion to 87 countries, comprising 3.3 per cent of their total humanitarian funding. CERF more frequently supplied aid to countries in North Africa and the Middle East, and to those that had suffered geophysical disasters. Appropriately, it funds vulnerable countries experiencing severe natural disasters, yet its funding may be affected by variables beyond severity and vulnerability. Further investigation is warranted, therefore.
A metabolic view of amphibian local community structure: the role of activation energy
Authors: Canavero Andrés , Arim Matías , Pérez Fernanda , Jaksic Fabián M. , Marquet Pablo A.
Published: January 2017

In the context of the metabolic theory of ecology (MTE), the activation energy (E) reflects the temperature dependence of metabolism and organism performance in different activities, such as calling behavior. In this contribution we test the role of temperature in affecting local amphibian community structure, particularly the number of species engaged in calling behavior across a temperature gradient. Toward this aim, we compiled phenological calling activity for 52 Neotropical anuran communities. For each community we estimated the activation energy of calling behavior (E), finding values significantly higher than previous reports. A wide range of methodological issues with the potential to produce overestimated E‐values were shown to have no significant effect on reported E‐values, supporting a biological interpretation of their high values and of geographic trends. Further, a path analysis related variation in E among communities with communities’ phylogenetic structure, local environmental conditions, richness, and seasonality. The decrease of activation energy at higher latitudes and less productive environments suggests that amphibians’ activity could become more dependent of internal individuals’ resources once external sources are reduced. The increase in phylogenetic attraction with latitude points to a rise in the role of niche conservatism and community filtering operating over conserved traits. Finally, flexibility in activation energy related to amphibians’ calling could be an important and poorly recognized determinant of their thermal dependence. The temporal structuring of amphians’ communities was related here with the interplay between ecological and evolutionary processes operating at different scales. Our results support the view of activation energy as an important parameter of biodiversity organization, which unravels the effects of ecological and evolutionary processes on biodiversity structure and function.
Cave Stedocys spitting spiders illuminate the history of the Himalayas and southeast Asia
Authors: Luo Yufa , Li Shuqiang
Published: January 2017

Stedocys spitting spiders (Araneae: Scytodidae) inhabit subterranean environments and have poor dispersal abilities. The Cenozoic Indian–Eurasian collision affected the regional biota of this genus, which occurs in parts of Indochina. Phylogeographical pattern of Stedocys based on multigene DNA sequence datasets reveals how tectonic history drove four biological splits. The first split dates to the late Paleocene–Eocene and involves the Truong Son Mountain Range and Mekong River. The other splits associate with the Eocene–Oligocene transition, including the Tonkin (Beibu) Gulf, the Ma River, and the Red River. These events indicate four early uplifts of the Himalayas and Tibetan Plateau. Our results cannot reject the hypothesis that uplifting of the Himalayas and Tibetan Plateau region due to crustal thickening and the lateral extrusion of Indochina occurred synchronously during the Paleocene–Oligocene transition in reaction to the Indian–Eurasian collision. Species of Stedocys cluster into groups I and II. Their evolution involves one dispersal and four vicariance events, which formed the following five Indochinese clades: Hainan clade (I‐1); western Yunnan and central Laos clade (I‐2); central Vietnam clade (I‐3); northern Vietnam and southwestern China clade (I‐4); and Thailand clade (II‐1). The lateral extrusion of Indochina is the driver of these events. The drifting of Hainan Island to its present location owes to its southeastern movement from continental Vietnam and Guangxi, China around the Eocene–Oligocene boundary. This biogeographical pattern highlights the significant role geography plays in shaping evolutionary history in southeastern Asia. It also illuminates how the timing of geological events drives the distributions of species.
Oviposition site selection by a lepidopteran leafminer in response to heterogeneity of leaf surface conditions: structural traits and microclimates
Authors: AYABE YOSHIKO , MINOURA TETSUAKI , HIJII NAOKI
Published: January 2017

1. Leafminer larvae are sedentary and make feeding tracks called mines. Their spatial distribution in trees affects their growth and survival through interaction with the heterogeneity of environments, such as leaf traits and microclimate. Lepidopteran leafminers that mine lower leaf surfaces have shown evolutionary radiation, suggesting that lower surfaces improve leafminer performance.

2. The lepidopteran multivoltine leafminer Phyllocnistis sp. Zeller (Gracirallidae: Phyllocnistinae) uses the Japanese privet Ligustrum japonicum Thunb. (Oleaceae). It mines only the lower‐surface epidermal layer of primary shoot leaves early in the occurrence season, but once lammas shoots appear, which happens in seasons other than spring, it preferentially uses the lower surface, but also uses the upper surface of the leaves. This study examined whether selection of oviposition sites was associated with the structural traits and microclimate of the leaf surface.

3. The shift of oviposition site from primary to lammas shoot leaves followed increasing hardness and epidermal cell wall thickness of primary shoot leaves during leaf development, and mine initiation rates decreased below 20% after oviposition on mature primary shoot leaves. Preference for the lower surface was related to the thinner cuticle. However, the thinner cuticle of the upper surface on lammas shoot leaves allowed Phyllocnistis sp. to expand its mining sites to both surfaces with no decrease in mine initiation and emergence rates.

4. Microclimates (leaf surface and mine temperatures) did not differ between upper and lower surfaces, suggesting that microclimate did not affect oviposition site selection by Phyllocnistis sp. These results suggest that the adaptive radiation of lower‐surface mining may have been influenced by the leaf surface characteristics.
Tree diversity in relation to maximum tree height: evidence for the harshness hypothesis of species diversity gradients
Authors: Marks Christian O. , Muller‐Landau Helene C. , Tilman David
Published: January 2017

Marks et al. (Ecology Letters, 19, 2016, 743) showed tree species richness correlates with maximum tree height, and interpret this as evidence that the environmental stressors that limit tree height also act as ecological filters on species richness. Here, we strengthen these arguments by further addressing the roles of environmental covariates and beta diversity.
Evolutionary toxicology in an omics world
Authors: Oziolor Elias M. , Bickham John W. , Matson Cole W.
Published: January 2017

Evolutionary toxicology is a young field that has grown rapidly in the past two decades. The potential of this field comes from the ability to link chemical contamination to multigenerational and population‐wide effects in various species. The advancements and rapidly decreasing costs of ‐omic tools are improving the power and resolution of evolutionary toxicology studies. In this manuscript, we aim to address the trajectories and perspectives for conducting evolutionary toxicology studies with ‐omic approaches. We discuss the complementarity of using multiple ‐omic tools (genomics, eDNA, transcriptomics, proteomics, and metabolomics) for utility in understanding the toxicological relevance of adaptive responses in populations. In addition, we discuss phenotypic plasticity and its relevance to transcriptomic studies in toxicology. As evolutionary toxicology grows and expands its capacity to link toxicology with population‐wide end points, we emphasize the applications of such studies in answering questions about ecological and population health, as well as future applicability to regulation. Thus, we aim to emphasize the enormous potential for evolutionary toxicology in an ‐omics world and give perspectives on the directions of future investigations.
Reduction and external coaptation as successful treatment for tarsocrural joint luxation in an Arabian mare
Authors: Maitland‐Stuart S. , Zeiler G. E. , Mahne A. T.
Published: January 2017

A 4‐year‐old Arabian mare was presented for evaluation of a suspected right tarsal luxation. Radiographs of the affected area revealed a tarsocrural joint luxation with an associated fractured lateral tibial malleolus. Under general anaesthesia, the fractured lateral malleolus was surgically removed via an arthrotomy and the luxation reduced. A full‐limb fibreglass cast was then placed. Recovery from anaesthesia was assisted with a tail rope. The limb was immobilised for 8 weeks with a cast. The mare made a good recovery and was used as a broodmare 18 months later, despite osteoarthritis affecting the joint.
Hypoproteinemia as a prognostic risk factor for arteriovenous fistula failure
Authors: Premuzic Vedran , Hudolin Tvrtko , Pasini Josip , Zimak Zoran , Hauptman Dinko , Jelakovic Bojan , Kastelan Zeljko
Published: January 2017

Introduction: Any vascular access is of limited duration with many factors which influence survival in patients on chronic hemodialysis (HD). Hypoproteinemia as a marker of chronic illness is common among chronic HD patients. Our aim was to analyze the survival of the primary arteriovenous fistula (AVFs) and the risk factors which influence their patency and to test the hypothesis that patients with normal values of serum proteins have lower risk of AVF failure compared to patients with hypoproteinemia.

Methods: Seven hundred thirty‐four consecutive patients were included who underwent creation of an AVF. The patients were prospectively followed‐up for 2 years. Only patients with AVF function after a month from its creation were analyzed. The patients were divided into two subgroups, with normal and low serum protein levels (<65 g/L).

Findings: At follow‐up 497 (67.7%) AVFs were still functional while 237 (32.3%) AVFs failed due to thrombosis or stenosis. Serum proteins and AVFs created on the forearm were positive predictors while diabetes was a negative predictor of longer AVF survival (P < 0.001; P = 0.003; P = 0.043). When comparing patients with normal and low serum protein levels (<65 g/L), mean survival time was significantly longer in patients with normal serum levels (P < 0.001).

Discussion: In this study, hypoproteinemia was an independent prognostic marker for AVF failure at 2 years. Hypoproteinemia, based on our results, is an independent, more sensitive and prognostic marker of possible vascular access failure than the presence of other common factors which influence shorter AVF survival.
Diet‐Induced Obesity Enhances TRPV1‐Mediated Neurovascular Reactions in the Dura Mater
Authors: Marics Balázs , Peitl Barna , Pázmándi Kitti , Bácsi Attila , Németh József , Oszlács Orsolya , Jancsó Gábor , Dux Mária
Published: January 2017

Objective

Exploring the pathophysiological changes in transient receptor potential vanilloid 1 (TRPV1) receptor of the trigeminovascular system in high‐fat, high‐sucrose (HFHS) diet‐induced obesity of experimental animals.

Background

Clinical and experimental observations suggest a link between obesity and migraine. Accumulating evidence indicates that metabolic and immunological alterations associated with obesity may potentially modulate trigeminovascular functions. A possible target for obesity‐induced pathophysiological changes is the TRPV1/capsaicin receptor which is implicated in the pathomechanism of headaches in a complex way.

Methods

Male Sprague‐Dawley rats were fed a regular (n = 25) or HFHS diet (n = 26) for 20 weeks. At the end of the dietary period, body weight of the animals was normally distributed in both groups and it was significantly higher in animals on HFHS diet. Therefore, experimental groups were regarded as control and HFHS diet‐induced obese groups. Capsaicin‐induced changes in meningeal blood flow and release of calcitonin gene‐related peptide (CGRP) from dural trigeminal afferents were measured in control and obese rats. The distribution of TRPV1‐ and CGRP‐immunoreactive meningeal sensory nerves was also compared in whole mount preparations of the dura mater. Metabolic parameters of the animals were assessed by examining glucose and insulin homeostasis as well as plasma cytokine concentrations.

Results

HFHS diet was accompanied by reduced food consumption and greater fluid and energy intakes in addition to increased body weight of the animals. HFHS diet increased fasting blood glucose and insulin concentrations as well as levels of circulating proinflammatory cytokines interleukin‐1β and interleukin‐6. In obese animals, dural application of the archetypal TRPV1 agonist capsaicin resulted in significantly augmented vasodilatory and vasoconstrictor responses as compared to controls. Diet‐induced obesity was also associated with enhanced basal and capsaicin‐induced CGRP release from meningeal afferents ex vivo. Except for minor morphological changes, the distribution of dural TRPV1‐ and CGRP‐immunoreactive afferents was similar in control and obese animals.

Conclusions

Our results suggest that obesity induced by long‐term HFHS diet results in sensitization of the trigeminovascular system. Changes in TRPV1‐mediated vascular reactions and CGRP release are pathophysiological alterations that may be of relevance to the enhanced headache susceptibility of obese individuals.
The clinicopathologic significance of lymphocyte subsets in acute myeloid leukemia
Authors: Alcasid M. , Ma L. , Gotlib J. R. , Arber D. A. , Ohgami R. S.
Published: January 2017

Introduction

While the role of the immune system in altering and modulating the progression of solid tumors is well studied, the impact of the immune system on the outcome and progression of hematolymphoid neoplasms is still poorly understood.

Methods

Here, we report a retrospective study detailing our analysis of 130 patients with acute myeloid leukemia (AML), with flow cytometry immunophenotypic evaluation of major lymphocyte subsets including B cells, T cells, and NK cells.

Results

Our study identifies differential signatures of lymphocyte subsets pertaining to distinct subcategories of AML, and prognostic correlations in patients. In multivariate analysis, NK cells (specifically CD56+/CD16+ NK cells at a cutoff of ≥5%) were found to be an independent indicator of improved overall and disease‐free survival; cytogenetic risk was also shown to be critical in stratifying patients with AML.

Conclusions

In total, we demonstrate that in AML, the subset distribution of immune system lymphocytes is nonrandom, and suggest an important role for distinct lymphocyte subsets, particularly NK cells, in this disease.
Simultaneous detection of 45 fusion genes in leukemia by dual‐color fluorescence real‐time PCR
Authors: Zheng Z. , Zhang P. , He G. , Liao K. , Wang Z. , Pan J. , Du K. , Du J. , Li B.‐A.
Published: January 2017

Introduction

Detection of recurrent genetic abnormalities is of great significance for a refined diagnosis and assessment of prognosis in leukemia. Conventional nested reverse transcription PCR is labor intensive and time‐consuming.

Methods

We have developed a novel dual‐color TaqMan probe‐based real‐time PCR method for the simultaneous screening of 45 fusion transcripts in 12 parallel reactions. The method was tested and validated with cell lines carrying known fusion transcripts and patient samples.

Results

A multiplex real‐time PCR method was successfully developed for rapid detection of 45 fusion genes and validated for 15 of the more commonly detected fusion genes. Intra‐assay reproducibility assessed for the most frequent rearrangements ranged from 0.41% to 0.74% for the coefficient of variation (CV) of cycle threshold (Ct) and the interassay reproducibility ranged from 1.62% to 2.83% in five separate experiments. The lowest detection limit for the translocations tested ranged between 1 : 16 000 and 1 : 32 000. Validation of the method with 213 patient samples showed 100% specificity and excellent consistence with conventional nested RT‐PCR.

Conclusion

Overall, we believe that this method is easily applicable, cost‐effective, and clinically useful for a rapid screening of fusion genes in the initial diagnostic phase of leukemia. Its use can also be extended to the monitoring of minimal residual disease.
Molecular basis of pyruvate kinase deficiency among Tunisians: description of new mutations affecting coding and noncoding regions in the PKLR gene
Authors: Jaouani M. , Manco L. , Kalai M. , Chaouch L. , Douzi K. , Silva A. , Macedo S. , Darragi I. , Boudriga I. , Chaouachi D. , Fitouri Z. , Van Wijk R. , Ribeiro M. L. , Abbes S.
Published: January 2017

Introduction

Pyruvate kinase (PK) deficiency is one of the most common hereditary nonspherocytic hemolytic anemias worldwide with clinical manifestations ranging from mild to severe hemolysis. However, investigation of this enzymopathy is lacking in Tunisia. We report here a pioneer investigation of PK deficiency among Tunisian cases referred to our laboratory for biological analysis of unknown cause of hemolytic anemia.

Methods

Two hundred and fifty‐three patients with unknown cause of hemolytic anemia have been addressed to our laboratory in order to investigate for red blood cells genetic disorders. Red cell enzyme activities were measured by standard methods, and molecular analysis was performed by DNA sequencing. The interpretation of mutation effect and the molecular modeling were performed by using specific software.

Results

Six different PKLR mutations were found (c.966‐1G>T; c.965+1G>A; c.721G>T; c.1163C>A; c.1456C>T; c.1537T>A), among which four are described for the first time. Genotype–phenotype correlations for the novel missense mutations were investigated by three‐dimensional structure analysis.

Conclusion

This study provides important data of PK deficiency among Tunisians. It might be followed by a large neonatal screening to determine the spectrum of PK mutations and identify potential deficient patients for an early medical follow‐up.
Antibodyomics: bioinformatics technologies for understanding B‐cell immunity to HIV‐1
Authors: Kwong Peter D. , Chuang Gwo‐Yu , DeKosky Brandon J. , Gindin Tatyana , Georgiev Ivelin S. , Lemmin Thomas , Schramm Chaim A. , Sheng Zizhang , Soto Cinque , Yang An‐Suei , Mascola John R. , Shapiro Lawrence
Published: January 2017

Numerous antibodies have been identified from HIV‐1‐infected donors that neutralize diverse strains of HIV‐1. These antibodies may provide the basis for a B cell‐mediated HIV‐1 vaccine. However, it has been unclear how to elicit similar antibodies by vaccination. To address this issue, we have undertaken an informatics‐based approach to understand the genetic and immunologic processes controlling the development of HIV‐1‐neutralizing antibodies. As DNA sequencing comprises the fastest growing database of biological information, we focused on incorporating next‐generation sequencing of B‐cell transcripts to determine the origin, maturation pathway, and prevalence of broadly neutralizing antibody lineages (Antibodyomics1, 2, 4, and 6). We also incorporated large‐scale robotic analyses of serum neutralization to identify and quantify neutralizing antibodies in donor cohorts (Antibodyomics3). Statistical analyses furnish another layer of insight (Antibodyomics5), with physical characteristics of antibodies and their targets through molecular dynamics simulations (Antibodyomics7) and free energy perturbation analyses (Antibodyomics8) providing information‐rich output. Functional interrogation of individual antibodies (Antibodyomics9) and synthetic antibody libraries (Antibodyomics10) also yields multi‐dimensional data by which to understand and improve antibodies. Antibodyomics, described here, thus comprise resolution‐enhancing tools, which collectively embody an information‐driven discovery engine aimed toward the development of effective B cell‐based vaccines.
Native‐like Env trimers as a platform for HIV‐1 vaccine design
Authors: Sanders Rogier W. , Moore John P.
Published: January 2017

We describe the development and potential use of various designs of recombinant HIV‐1 envelope glycoprotein trimers that mimic the structure of the virion‐associated spike, which is the target for neutralizing antibodies. The goal of trimer development programs is to induce broadly neutralizing antibodies with the potential to intervene against multiple circulating HIV‐1 strains. Among the topics we address are the designs of various constructs; how native‐like trimers can be produced and purified; the properties of such trimers in vitro and their immunogenicity in various animals; and the immunization strategies that may lead to the eventual elicitation of broadly neutralizing antibodies. In summary, native‐like trimers are a now a platform for structure‐ and immunology‐based design improvements that could eventually yield immunogens of practical value for solving the long‐standing HIV‐1 vaccine problem.
Identification and specificity of broadly neutralizing antibodies against HIV
Authors: McCoy Laura E. , Burton Dennis R.
Published: January 2017

Beginning in 2009, studies of the humoral responses of HIV‐positive individuals have led to the identification of scores, if not hundreds, of antibodies that are both broadly reactive and potently neutralizing. This development has provided renewed impetus toward an HIV vaccine and led directly to the development of novel immunogens. Advances in identification of donors with the most potent and broad anti‐HIV serum neutralizing responses were crucial in this effort. Equally, development of methods for the rapid generation of human antibodies from these donors was pivotal. Primarily these methods comprise single B‐cell culture coupled to high‐throughput neutralization screening and flow cytometry‐based sorting of single B cells using HIV envelope protein baits. In this review, the advantages and disadvantages of these methodologies are discussed in the context of the specificities targeted by individual antibodies and the need for further improvements to evaluate HIV vaccine candidates.
B‐cell responses to HIV infection
Authors: Moir Susan , Fauci Anthony S.
Published: January 2017

The induction of neutralizing antibodies directed against the human immunodeficiency virus (HIV) has received considerable attention in recent years, in part driven by renewed interest and opportunities for antibody‐based strategies for prevention such as passive transfer of antibodies and the development of preventive vaccines, as well as immune‐based therapeutic interventions. Advances in the ability to screen, isolate, and characterize HIV‐specific antibodies have led to the identification of a new generation of potent broadly neutralizing antibodies (bNAbs). The majority of these antibodies have been isolated from B cells of chronically HIV‐infected individuals with detectable viremia. In this review, we provide insight into the phenotypic and functional attributes of human B cells, with a focus on HIV‐specific memory B cells and plasmablasts/cells that are responsible for sustaining humoral immune responses against HIV. We discuss the abnormalities in B cells that occur in HIV infection both in the peripheral blood and lymphoid tissues, especially in the setting of persisting viremia. Finally, we consider the opportunities and drawbacks of intensively interrogating antibodies isolated from HIV‐infected individuals to guide strategies aimed at developing effective antibody‐based vaccine and therapeutic interventions for HIV.
Systems serology for evaluation of HIV vaccine trials
Authors: Ackerman Margaret E. , Barouch Dan H. , Alter Galit
Published: January 2017

The scale and scope of the global epidemic, coupled to challenges with traditional vaccine development approaches, point toward a need for novel methodologies for HIV vaccine research. While the development of vaccines able to induce broadly neutralizing antibodies remains the ultimate goal, to date, vaccines continue to fail to induce these rare humoral immune responses. Conversely, growing evidence across vaccine platforms in both non‐human primates and humans points to a role for polyclonal vaccine‐induced antibody responses in protection from infection. These candidate vaccines, despite employing disparate viral vectors and immunization strategies, consistently identify a role for functional or non‐traditional antibody activities as correlates of immunity. However, the precise mechanism(s) of action of these “binding” antibodies, their specific characteristics, and their ability to be selectively induced and/or potentiated to result in complete protection merits parallel investigation to neutralizing antibody‐based vaccine design approaches. Ultimately, while neutralizing and functional antibody‐based vaccine strategies need not be mutually exclusive, defining the specific characteristics of “protective” functional antibodies may provide a target immune profile to potentially induce more robust immunity against HIV. Specifically, one approach to guide the development of functional antibody‐based vaccine strategies, termed “systems serology”, offers an unbiased and comprehensive approach to systematically survey humoral immune responses, capturing the array of functions and humoral response characteristics that may be induced following vaccination with high resolution. Coupled to machine learning tools, large datasets that explore the “antibody‐ome” offer a means to step back from anticipated correlates and mechanisms of protection and toward a more fundamental understanding of coordinated aspects of humoral immune responses, to more globally differentiate among vaccine candidates, and most critically, to identify the features of humoral immunity that distinguish protective from non‐protective responses. Overall, the systematic serological approach described here aimed at broadly capturing the enormous biodiversity in antibody profiles that may emerge following vaccination, complements the existing cutting edge tools in the cellular immunology space that survey vaccine‐induced polyfunctional cellular activity by flow cytometry, transcriptional profiling, epigenetic, and metabolomic analysis to offer a means to develop both a more nuanced and a more complete understanding of correlates of protection to support the design of functional vaccine strategies.
Survivors Remorse: antibody‐mediated protection against HIV‐1
Authors: Lewis George K. , Pazgier Marzena , DeVico Anthony L.
Published: January 2017

It is clear that antibodies can play a pivotal role in preventing the transmission of HIV‐1 and large efforts to identify an effective antibody‐based vaccine to quell the epidemic. Shortly after HIV‐1 was discovered as the cause of AIDS, the search for epitopes recognized by neutralizing antibodies became the driving strategy for an antibody‐based vaccine. Neutralization escape variants were discovered shortly thereafter, and, after almost three decades of investigation, it is now known that autologous neutralizing antibody responses and their selection of neutralization resistant HIV‐1 variants can lead to broadly neutralizing antibodies in some infected individuals. This observation drives an intensive effort to identify a vaccine to elicit broadly neutralizing antibodies. In contrast, there has been less systematic study of antibody specificities that must rely mainly or exclusively on other protective mechanisms, although non‐human primate (NHP) studies as well as the RV144 vaccine trial indicate that non‐neutralizing antibodies can contribute to protection. Here we propose a novel strategy to identify new epitope targets recognized by these antibodies for which viral escape is unlikely or impossible.
Use of broadly neutralizing antibodies for HIV‐1 prevention
Authors: Pegu Amarendra , Hessell Ann J. , Mascola John R. , Haigwood Nancy L.
Published: January 2017

Antibodies have a long history in antiviral therapy, but until recently, they have not been actively pursued for HIV‐1 due to modest potency and breadth of early human monoclonal antibodies (MAbs) and perceived insurmountable technical, financial, and logistical hurdles. Recent advances in the identification and characterization of MAbs with the ability to potently neutralize diverse HIV‐1 isolates have reinvigorated discussion and testing of these products in humans, since new broadly neutralizing MAbs (bnMAbs) are more likely to be effective against worldwide strains of HIV‐1. In animal models, there is abundant evidence that bnMAbs can block infection in a dose‐dependent manner, and the more potent bnMAbs will allow clinical testing at infusion doses that are practically achievable. Moreover, recent advances in antibody engineering are providing further improvements in MAb potency, breadth, and half‐life. This review summarizes the current state of the field of bnMAb protection in animal models as well as a review of variables that are critical for antiviral activity. Several bnMAbs are currently in clinical testing, and we offer perspectives on their use as pre‐exposure prophylaxis (PrEP), potential benefits beyond sterilizing immunity, and a discussion of future approaches to engineer novel molecules.
Safety and efficacy of intramuscular human placenta‐derived mesenchymal stromal‐like cells (cenplacel [PDA‐002]) in patients who have a diabetic foot ulcer with peripheral arterial disease
Authors: Wu Stephanie C , Pollak Richard , Frykberg Robert G , Zhou Wei , Karnoub Maha , Jankovic Vladimir , Fischkoff Steven A , Chitkara Denesh
Published: January 2017

The objective of this study was to examine the safety of cenplacel (PDA‐002) in patients with peripheral arterial disease (PAD) and a diabetic foot ulcer (DFU). Cenplacel is a mesenchymal‐like cell population derived from full‐term human placenta. This phase 1, dose‐escalation study investigated cenplacel in diabetic patients with chronic DFUs (Wagner grade 1 or grade 2) and PAD [ankle‐brachial index (ABI) >0·5 and ≤0·9], enrolled sequentially into each of four dose cohorts (3 × 106, 10 × 106, 30 × 106 and 100 × 106 cells; administered intramuscularly on study days 1 and 8 in combination with standard of care). Overall, cenplacel was well tolerated in all 15 patients in the study. Before enrollment, nine patients had an ulcer for ≥6 months and 11 had an ABI of 0·7–0·85. No patient met dose‐limiting toxicity criteria and no treatment‐related serious adverse events were reported. There was preliminary evidence of ulcer healing in seven patients (five complete; two partial) within 3 months of cenplacel treatment, and circulating endothelial cell levels (a biomarker of vascular injury in PAD) were decreased within 1 month. Cenplacel was generally safe and well tolerated in patients with chronic DFUs and PAD. Outcomes from this study informed the doses, endpoints, biomarkers and patient population for an ongoing phase 2 trial.
Healthy food choice: Survey results from Iranian consumers toward antibiotic‐free chicken
Authors: Rahnama Hassan , Fadaei Mehdi , Baghersalimi Saeed
Published: January 2017

Demand for healthy food is increasing in Iran. Although demand for these foods has increased, the real benefits and purchasing patterns are not known. The purpose of this study is to identify factors affecting consumer choice behavior toward antibiotic‐free chicken, and examines whether there are significant differences in importance of these factors between consumers with different outlooks. Logistic regression, chi‐square, and Friedman test were applied to assess collected data by a questionnaire survey. The results indicated that perception, awareness, motivation, social factors, and lifestyle had significant influence on the choice of antibiotic‐free chicken and demographic factors had no influence on it. Among effective factors, perception, and motivation have the most and least effect on choice of antibiotic‐free chicken, respectively.

Practical applications

These results are relevant to sensory scientists and healthy foods producers, especially antibiotic‐free chicken producers are interested to know how different factors will be able to impact on consumers' choice behavior. There is less information in the literature about consumer choice behavior toward antibiotic‐free chicken in Iran and another country. A better understanding of consumer choice behavior can be beneficial to develop this kind of product, and help poultry industry activists to encourage consumer to buy healthy products. The study showed that consumers' perception including high quality, appropriate packaging, cleanness of store, and credible brand are the most influential factors on consumer choice behavior. The researchers' findings might suggest the importance of social factors and raise of awareness as another important factors through consumers approach.